Received: 31 March 2019 Revised: 24 July 2019 Accepted: 1 August 2019

DOI: 10.1002/glia.23706

REVIEW ARTICLE

The fate and function of oligodendrocyte progenitor cells

after traumatic spinal cord injury

Greg J. Duncan1 | Sohrab B. Manesh2 | Brett J. Hilton3 | Peggy Assinck4 |

Jason R. Plemel5 | Wolfram Tetzlaff2,6

1
Department of Neurology, Jungers Center for
Neurosciences Research, Oregon Health and Abstract
Science University, Portland, Oregon Oligodendrocyte progenitor cells (OPCs) are the most proliferative and dispersed
2
Graduate Program in Neuroscience,
population of progenitor cells in the adult central nervous system, which allows these
International Collaboration on Repair
Discoveries (ICORD), University of British cells to rapidly respond to damage. Oligodendrocytes and myelin are lost after trau-
Columbia (UBC), Vancouver, British Columbia,
matic spinal cord injury (SCI), compromising efficient conduction and, potentially, the
Canada
3
Deutsches Zentrum für Neurodegenerative long-term health of axons. In response, OPCs proliferate and then differentiate into
Erkrankungen (DZNE), Bonn, Germany new oligodendrocytes and Schwann cells to remyelinate axons. This culminates in
4
MRC Centre for Regenerative Medicine,
highly efficient remyelination following experimental SCI in which nearly all intact
University of Edinburgh, Edinburgh, UK
5
Department of Medicine, Division of
demyelinated axons are remyelinated in rodent models. However, myelin regenera-
Neurology, Neuroscience and Mental Health tion comprises only one role of OPCs following SCI. OPCs contribute to scar forma-
Institute, University of Alberta, Calgary,
Alberta, Canada
tion after SCI and restrict the regeneration of injured axons. Moreover, OPCs alter
6
Departments of Zoology and Surgery, their gene expression following demyelination, express cytokines and perpetuate the
University of British Columbia, Vancouver, immune response. Here, we review the functional contribution of myelin regenera-
British Columbia, Canada
tion and other recently uncovered roles of OPCs and their progeny to repair
Correspondence following SCI.
Wolfram Tetzlaff, International Collaboration
on Repair Discoveries (ICORD), University of
British Columbia, Blusson Spinal Cord Centre, KEYWORDS
818 West 10th Avenue, Vancouver, BC V5Z oligodendrocyte, oligodendrocyte progenitor cell, remyelination, Schwann cell, spinal cord
1M9, Canada. injury
Email: tetzlaff@icord.org

1 | I N T RO D UC T I O N
Traumatic spinal cord injuries (SCIs) often leave patients with permanent
sensory and motor disabilities alongside long-term health problems. The
pathobiology of SCI can be split into the initial trauma (primary damage)
followed by a secondary phase. The secondary phase of injury involves a
cascade of ischemia, inflammation, and cell death including, and of
importance in this review, oligodendrocytes (Crowe, Bresnahan, Shu-
man, Masters, & Beattie, 1997; Hilton, Moulson, & Tetzlaff, 2017; Kwon,
Tetzlaff, Grauer, Beiner, & Vaccaro, 2004; Norenberg, Smith, & Marcillo,
2004). Oligodendrocytes are susceptive to damage from reactive oxygen
species, excitotoxicity, extracellular ATP, and pro-inflammatory cyto-
kines all of which are present following SCI (Crowe et al., 1997; Giacci
Greg J. Duncan and Sohrab B. Manesh authors contributed equally to this work.
et al., 2018; Plemel et al., 2014). Preclinical data show that as the milieu
of the spinal cord becomes less toxic (Crowe et al., 1997; Williams et al.,
2014), a period of remyelination follows (Blight, 1985; Hesp, Goldstein,
Miranda, Kaspar, & McTigue, 2015; Powers et al., 2012). Even when
motor and sensory function is completely lost below the site of injury in
humans, the majority of injuries are anatomically incomplete (Kakulas,
1988) and up to a hundred thousand axons may be spared in humans
(Kakulas & Kaelan, 2015). Many of these surviving axons are stripped of
their myelin (demyelinated; Bunge, Puckett, Becerra, Marcillo, &
Quencer, 1993; Guest, Hiester, & Bunge, 2005; Norenberg et al., 2004)
likely due to the loss of oligodendrocytes. Accordingly, many have
hypothesized that myelin regeneration is a plausible therapeutic target
to promote signal conduction and protect axons from secondary damage
(Alizadeh, Dyck, & Karimi-Abdolrezaee, 2015; Myers, Bankston, Burke,

Glia. 2019;1–19. wileyonlinelibrary.com/journal/glia © 2019 Wiley Periodicals, Inc. 1

2 DUNCAN ET AL.
Ohri, & Whittemore, 2016; Papastefanaki & Matsas, 2015; Plemel et al.,
2014). However, there is no direct evidence that oligodendrocyte
remyelination contributes to the partial spontaneous functional recovery
after SCI. Despite this, transplantation of myelin-forming cells is/has
been used in several clinical trials of SCI (https://clinicaltrials.gov/).
Moreover, oligodendrocyte lineage cells have diverse roles follow-
ing traumatic SCI beyond oligodendrocyte remyelination. They pro-
duce remyelinating Schwann cells, contribute to glial scaring where
they alter the growth of axons and may even regulate immune
responses. Here, we describe the diverse roles that oligodendrocyte
lineage cells play in the lesion environment with a focus on how these
roles may contribute to the spontaneous locomotor recovery
observed after SCI.
1.1 | OPCs during development and in adulthood
During development, oligodendrocyte progenitor cells (OPCs; expre-
ssing the markers PDGFRα and NG2) are first observed in the ventricular
germinal zones of the brain and spinal cord at embryonic day 12.5
(E12.5) in mice (Huang, Guo, Bai, Scheller, & Kirchhoff, 2019; Pringle &
Richardson, 1993; Timsit et al., 1995; Warf, Fok-Seang, & Miller, 1991)
while a second wave of these cells originate from the dorsal cord at
E15.5 (Cai et al., 2005; Fogarty, Richardson, & Kessaris, 2005; Vallstedt,
Klos, & Ericson, 2005). Ultimately, these two populations of OPCs dis-
play similar properties (Marques et al., 2018; Tripathi et al., 2011) and
both differentiate to form the myelinating cell of the central nervous sys-
tem (CNS), the oligodendrocyte. However, there is some heterogeneity
during adulthood in the electrophysiological properties of OPCs
depending on the region of the CNS in which they are located (Foerster,
Hill, & Franklin, 2019; Spitzer et al., 2019; van Bruggen, Agirre, &
Castelo-Branco, 2017).
In the adult, OPCs tile throughout the entire CNS through a mech-
anism of self-repulsion (Hughes, Kang, Fukaya, & Bergles, 2013).
Branching and highly motile filopodia survey the environment to allow
OPCs to quickly detect and replace lost or differentiated OPCs (Hill,
Patel, Goncalves, Grutzendler, & Nishiyama, 2014; Hughes et al.,
2013). Additionally, OPCs also form close connections with neurons
which allow them to monitor changes in neuronal activity (Bergles,
Roberts, Somogyi, & Jahr, 2000; Gallo, Mangin, Kukley, & Dietrich,
2008; Hill et al., 2014; Hughes et al., 2013). These connections have
properties similar to traditional neuron–neuron synapses, including
accumulation of vesicles in presynaptic terminals apposed from OPCs,
expression of neurotransmitter receptors on OPCs akin to postsynap-
tic neurons, release of vesicles into the intersynaptic space, and sub-
sequent fast-kinetic currents in OPCs (Bergles et al., 2000; Gallo et al.,
1996; Hamilton et al., 2017; Karadottir, Hamilton, Bakiri, & Attwell,
2008; Kukley, Capetillo-Zarate, & Dietrich, 2007; Ziskin, Nishiyama,
Rubio, Fukaya, & Bergles, 2007), and has been thoroughly reviewed
elsewhere (Almeida & Lyons, 2014; Bergles, Jabs, & Steinhauser,
2010; de Faria Jr., Pama, Evans, Luzhynskaya, & Karadottir, 2018). In
parallel to development where OPCs have synaptic input from unmy-
elinated axons (Kukley et al., 2007; Ziskin et al., 2007), demyelination
increases excitatory currents within OPCs, which are suppressed by
the administration of tetrodotoxin (a voltage-gated sodium channel
blocker) to block neuronal activity (Gautier et al., 2015). While few
studies have modulated these synapse-like connections between
neurons and OPCs in vivo during traumatic injury or demyelination,
administration of tetrodotoxin or α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid receptor (AMPAR) inhibitors impairs
remyelination (Gautier et al., 2015). Synaptic connections also form
between NG2+ glia and dystrophic axons after SCI, and might restrict
axon growth (Filous et al., 2014) and is thoroughly discussed below.
OPCs are persistently monitoring their environment and are highly
responsive to changes in neurons in health and disease.
OPCs form oligodendrocytes not only during development, but
also throughout adulthood (Hill, Li, & Grutzendler, 2018; Hughes,
Orthmann-Murphy, Langseth, & Bergles, 2018; Young et al., 2013). In
addition to de-novo oligodendrocytes, changes to established myelin
occurs throughout life and can modulate axonal conductance. In vivo
imaging using label-free spectral confocal reflectance microscopy
showed ~19% of established myelin sheaths either retract or extend
during adulthood in mice (Hill et al., 2018). The thickness of individual
myelin sheaths can change as well: overactivation of mTOR signaling
in adult oligodendrocytes increases myelin thickness and wrap num-
ber (Snaidero et al., 2014), optogenetic or chemogenetic activation of
neurons enhances the thickness of their myelin (Gibson et al., 2014;
Mitew et al., 2018), whereas social isolation reduces adult myelination
of the prefrontal cortex (Liu et al., 2012; Makinodan, Rosen, Ito, &
Corfas, 2012). However, whether myelin sheaths can become thinner
is not well-established. Cleavage of neurofascin 155 by thrombin at
the paranode reduces myelin thickness and increases nodal size and
may be blocked by astrocytic exocytosis of thrombin protease inhibi-
tors (Dutta et al., 2018). The idea that perinodal astrocytes can modu-
late myelin dynamics is very novel, but whether such a mechanism is
critical for adaptive changes in myelin is still yet to be determined. An
additional possibility is that breakdown of the blood brain barrier
(BBB) during SCI or in MS lesions, may result in vascular thrombin
entering the parenchyma and inducing cleavage of NF155 breaking
the connection of the paranodal loops to the axon, and possibly
resulting in demyelination. Whether such a mechanism drives demye-
lination following SCI, requires explicit validation. Nevertheless, there
is now compelling data that myelination is highly dynamic throughout
adulthood and can be changed in response to environment stimuli and
learning paradigms.
1.2 | Oligodendrocytes support axonal health and
function
1.2.1 | Myelin and conduction
Myelin facilitates rapid signal conduction in axons. As a multilamellar
membrane, myelin increases the resistance and lowers the capaci-
tance of the nerve fiber. These insulating properties allow for rapid
impulse propagation, with current being reinitiated at the unmyelin-
ated nodes of Ranvier in a process called “saltatory conductance”
(Lillie, 1925). This permits the rapid propagation of action potentials in
DUNCAN ET AL.
even relatively small caliber axons, minimizing the space necessary for
fast conduction of signals. Subtle myelin changes can also fine tune
impulse propagation. Factors such as internodal length, myelin thick-
ness, or partial myelination of single axons can be modulated to alter
conduction velocity throughout life (Etxeberria et al., 2016; Ford
et al., 2015; Hill et al., 2018; Hughes et al., 2018). After SCI, demyelin-
ation may silence or slow action potential propagation (Blight, 1983a;
Hains, Saab, Lo, & Waxman, 2004; James et al., 2011; Nashmi & Feh-
lings, 2001) and potentially contribute to functional deficits.
It is still unclear the extent to which conduction failure after SCI stems
from demyelination or other factors. Acutely after SCI, even when axons
are spared, conduction within the spinal cord is severely diminished and
correlates with temporary loss of spinal cord reflexes in humans, a poorly
understood mechanism termed clinically as spinal shock (Atkinson &
Atkinson, 1996; James et al., 2011; Smith & Jeffery, 2005). Within the
first 2 weeks, electrophysiological recordings of the spinal cord show at
least some conduction is restored (Beaumont, Onifer, Reed, & Magnuson,
2006; Hains et al., 2004; Hubscher & Johnson, 2006; James et al., 2011;
Metz et al., 2000). This is, however, temporally discordant with oligoden-
drocyte remyelination, which largely occurs after the first 2 weeks in
experimental models (Figure 1; Duncan, Manesh, et al., 2018; James et al.,
2011), though it is plausible that later improvements in the speed of con-
duction are derived from remyelination. However, conduction block can
also be mediated by nitric oxide and extracellular molecules like NG2
released in the wake of trauma (Hunanyan et al., 2010; Redford, Kapoor, &
Smith, 1997; Shrager, Custer, Kazarinova, Rasband, & Mattson, 1998).
Intraspinal injections of anti-NG2 antibodies resulted in improved axonal
conductance in a chronic hemisection injury model (Petrosyan et al.,
2013). Compounded with the ability of demyelinated axons to eventually
conduct without myelin (Felts, Baker, & Smith, 1997), and rather efficient
remyelination of axons in rodents (Duncan, Radcliff, et al., 2018; James
et al., 2011), it remains unclear whether demyelination is causing persis-
tent conduction deficits after SCI.
1.2.2 | Oligodendrocytes and trophic support
Axons project long distances from the neuronal cell body, which pre-
sents logistical challenges for energy production. Although myelin
reduces the energy requirements on the axon for repeated action
potentials, the overall metabolic requirements necessary to establish
and maintain myelinated axons is higher than developmentally unmy-
elinated axons when factoring in myelin genesis and maintenance of
oligodendrocyte resting potential (Harris & Attwell, 2012). Demyelin-
ation results in the redistribution and upregulation of ion channels
along the axon (England, Gamboni, & Levinson, 1991; England,
Gamboni, Levinson, & Finger, 1990). More specifically, Nav1.2, Nav
1.6, Na/Ca2+ exchanger, Kv1.1, and Kv1.2 expression is upregulated
and redistributed on demyelinated axons (Craner et al., 2004; Rasband
et al., 1998). Although normally confined to nodes of Ranvier and
juxtaparanode, these ion channels spread along the axon length fol-
lowing demyelination and increase the energy expenditure necessary
to repolarize the axolemma. Demyelination therefore shifts the energy
3
demands to the axons rather than spreading the ATP usage between
separate cells.
The increased energy demands of the demyelinated axon may cause
an energy crisis ultimately leading to their degeneration. If ATP demands
are not met, Na+/K+ ATPases will not effectively remove Na+ ions thus
reversing the Na/Ca exchanger and causing an influx of Ca2+ ions (Stys,
Waxman, & Ransom, 1991). This overload of intracellular Ca2+ ions acti-
vates calcium dependent systems such as calpains, which in turn can lead
to degradation of the cytoskeleton, compromising axonal structure
(Figure 2; Liu, Yin, Zhang, & Qian, 2014; Posmantur et al., 1997). Increases
to intracellular Ca2+ can also trigger a mitochondrial permeability transi-
tion that leads to depolarization of mitochondrial membranes, impairing
mitochondrial function, and contributing to axonal degeneration
(Bernardi, 1992; Lehninger, Vercesi, & Bababunmi, 1978). As many white
matter axons are frequently active, being forced to maintain and replenish
an ion gradient over such a large surface area can lead to ATP depletion
and a state of “virtual hypoxia” that eventually leads to axonal death (see
review by Trapp & Stys, 2009). Given the slow movement of molecules
within the cytoplasm (Oblinger, Foe, Kwiatkowska, & Kemp, 1988) and
that oligodendrocyte myelin physically separates axons from vasculature,
they must receive metabolites locally, at least during times of high-energy
demand (Nave, 2010). Although astrocytes physically contact myelinated
neurons, these interactions are limited to cell bodies, synapses, and nodes
of Ranvier, whereas oligodendrocytes make considerably more contact
with white matter axons along the entire internode. This puts oligoden-
drocytes in a favorable position to provide metabolic support to axons.
MCT1, a transporter of lactate, is highly enriched in oligodendrocytes and
its disruption is sufficient to cause axon loss (Lee et al., 2012). Metabolic
support from oligodendrocytes to axons is integral to their function and
merely impairing axon-oligodendrocyte interactions, even without out-
right demyelination, is often enough to induce axon loss (Edgar et al.,
2009; Griffiths et al., 1998; Snaidero et al., 2017). Collectively these data
make it clear that axons depend on oligodendrocytes for their function
and health, and oligodendrocyte deficiency may leave axons vulnerable
to loss.
However, it remains unclear if demyelination and oligodendrocyte
loss is driving axonal degeneration after SCI. Whether or not demye-
lination persists for long enough after SCI or whether the extent of
demyelination crosses this threshold to induce axon loss is unclear. If
demyelination persists in more chronic settings, mitochondrial DNA
damage and free radical production creates a vicious cycle increasing
the likelihood of axonal death due to a metabolic deficit (Campbell,
Worrall, & Mahad, 2014; Criste, Trapp, & Dutta, 2014). Through these
mechanisms, remyelination could prevent long-term damage to axons
following SCI.
1.3 | OPCs as multipotent progenitors after SCI
In adulthood, OPCs remain, as their name would indicate, as dedicated
progenitors of oligodendrocytes (Kang, Fukaya, Yang, Rothstein, &
Bergles, 2010; Young et al., 2013). However, after injury or a demye-
linating lesion, OPCs are activated and display extensive lineage plas-
ticity. Traditionally, OPCs have been identified by their expression of
4 DUNCAN ET AL.

(a) Healthy Adult CNS (b) Spinal Cord Injury

OPC/NG2+
OPC/NG2+ Myelin debris Reactive astrocyte

Axon Myelinating cells Scar formation

Oligodendrocyte New oligodendrocyte New myelinating

and associated Schwann cells Reactive
and associated
myelin sheaths astrocyte
myelin sheaths

(c) Uninjured (d) Acute SCI (e) Chronic SCI

(days-weeks post-injury) (months p
post-injury)

Rostral
Ros
Rostra
rall Rostral

Caudal Caudal
Rostral
Rostral

Rostral

Developmental Developmental
Developmental oligodendrocyte oligodendrocyte
oligodendrocyte myelin Ne myelin
w
myelin oli
g
epicentre
epicentre

epicentre

Injury

od r
Injury

Injury

Demyelinated Schwann
end

Axons cell myelin

oc
yte
mye
lin
Caudal
Caudal

Caudal

Myelin content on intact axons (>1mm) Myelin content on intact axons (>1mm) Myelin content on intact axons (>1mm)

F I G U R E 1 Following traumatic injury to the spinal cord, OPCs are multipotent and differentiate into cells capable of remyelination and contributing to
the glial scar. (a) Schematic indicating that OPCs are proliferative in the healthy adult CNS and are restricted to producing new oligodendrocytes.
(b) Following SCI, OPCs become multipotent differentiating into astrocytes, Schwann cells and oligodendrocytes. Both the proliferative rate and the number
of new oligodendrocytes increases after SCI. (c) Diagram of the uninjured spinal cord with oligodendrocyte lineage cells indicated within the spinal cord.
Axons represent descending supraspinal myelinated axons. Graphs below the spinal cord reveal the relative amount of myelin on intact axons that are
greater than 1 μm in diameter, which are typically myelinated, as well as its cellular source. (d) Acute injury (defined as days to several weeks post-SCI) results
in the transection of some axons, which form endbulbs with the distal segment beginning to undergo Wallerian-like degeneration. During the acute
timeframe, OPCs become activated and begin proliferating in response to injury but have not yet began to generate large numbers of new oligodendrocytes
or Schwann cells. (e) Chronically after SCI (defined as months following SCI), OPCs have formed new remyelinating oligodendrocytes along with Schwann
cells which effectively regenerate myelin along intact denuded axons. OPCs also contribute to glial scarring by forming some astrocytes
DUNCAN ET AL. 5

NG2 and PDGFRα (Nishiyama, Lin, Giese, Heldin, & Stallcup, 1996; labeling showed elevated numbers throughout the spinal cord in the
Pringle, Mudhar, Collarini, & Richardson, 1992; Raff, Lillien, Richard- first 4 weeks postinjury (McTigue, Wei, & Stokes, 2001). Similar stud-
son, Burne, & Noble, 1988; Richardson, Pringle, Mosley, ies also revealed BrdU co-labeling with CC1 (a marker of mature oligo-
Westermark, & Dubois-Dalcq, 1988), although these markers can be dendrocytes) and glial fibrillary acidic protein (GFAP, a marker of
expressed on other cell types, like perineurial fibroblasts and pericytes astrocytes) suggesting these cells constitute the majority of newly
(Assinck, Duncan, Plemel, et al., 2017; Kang et al., 2010). Assessment formed cells after injury (Zai & Wrathall, 2005). Indeed, within the first
of proliferation of NG2+ cells using bromodeoxyuridine (BrdU) 24 hr after injury, retrovirally labeled NG2+ progenitors contribute to
scar forming astrocytes, while those born after 7 days postinjury seem
to be mostly contributing to myelin-producing oligodendrocytes
(a) (Sellers, Maris, & Horner, 2009). More recently, fate mapping of
PDGFRα+ cells confirmed that most newly formed oligodendrocytes
after SCI are derived from OPCs (Assinck, Duncan, Plemel, et al.,
Uninjured
MCT1
2017; Hesp et al., 2015). Other groups have also found that 25% of
MCT1
ATP ATP P MCT2
CT2
ATP
AT
ATP ATP MCT2

Kvv
Nav
Kv
P
PP P
PP
PP P PP
PP PP
PP P
PP
PP P PP
PP
Nav
ATP NG2+ fate mapped cells form astrocytes by 4 weeks post-SCI com-
Kvv Kvv Kvv
Kvv PP PP PP PP PP PP Kvv Kv
Nav
PP P PP P PP PP P PP P PP Nav
PP
PP P
PP
PP P PP
PP pared to 9% seen in experimental autoimmune encephalomyelitis
duction (EAE; Hackett et al., 2016, 2018). OPC are less likely to become astro-
Con
cytes in other traumatic models of injury like dorsal column transec-
tions (Barnabe-Heider et al., 2010), and cortical stab injuries (Dimou,
(b) SCI Simon, Kirchhoff, Takebayashi, & Gotz, 2008). Together, these studies
indicate that the injury environment of contusive SCI may be more
conducive to diversity in OPC fate.
Demyelination
The myelin constituency of the spinal cord changes following injury.
OPCs have been shown to produce myelinating Schwann cells after
MCT1
ATP MCT2 chemical demyelination (Zawadzka et al., 2010) as well as following trau-
Kv
ATP
Kv Kv Kv Kv
Nav Kvv
Nav Nav Nav
ATP
Nav Kvv
ATP matic injuries (Assinck, Duncan, Plemel, et al., 2017; Bartus et al., 2019). A
duction population of protein zero (P0) positive Schwann cells derived from OPCs
Con
Myeli epair

appear to dominate the dorsal regions of the injured cord after dorsal con-
Sustained Myelin

tusion injuries (Assinck, Duncan, Plemel, et al., 2017). While, the majority
(c)
nR

of these Schwann cells are derived from PDGFRα-positive OPCs and are
myelinating axons in the spinal cord, both FOXJ1-expressing

Remyelination
MCT1 MCT1
1
MCT2 MCT1
MCT2
CT2
2 MCT2
ATP PP
PP P
PP
PP P
P
P PP
PP P
PP
PP P
PP

F I G U R E 2 Remyelination restores rapid conductance and

PP PP
ATP
AT
TP PP PP PP
Loss

Nav Nav
Kvv Kv Kvv Kv PP P PP P PP
Kvv Kvv Kvv Kvv
Nav PP PP PP Nav
ATP PP P PP P PP
ATP oligodendrocyte-derived trophic support to the axon. (a) Schematic of
an axon myelinated by oligodendrocytes. Voltage-gated sodium
nduction
Co
channels (Nav) and voltage-gated potassium (Kv) channels are located
at the node of Ranvier and juxtaparanode, respectively. The action
(d) potential is reinitiated at the node of Ranvier allowing for saltatory
conductance. Oligodendrocytes provide trophic support to axons by
shuttling lactate and/or pyruvate through MCT1 to the axon, which
Chronic Demyelination expresses MCT2. Myelinated axons are capable of plentiful ATP
production via their mitochondria, and use lower amounts of ATP to
ATP
propagate action potentials relative to unmyelinated axons.
Nav Kv Nav Kv Nav Kv Nav Kv Nav (b) Following SCI, demyelination occurs causing sodium and
potassium channels to spread along the denuded axolemma to
Condu
ction maintain conductance. Trophic support from oligodendrocytes is lost
and the axon requires more energy to propagate action potentials.
(c) Remyelination, which has characteristically short internodes and
thin myelin, restores rapid conduction to the axon. Nav and Kv
Nav voltage-gated sodium channel relocate back to the node and juxtaparanode, respectively. Trophic
Kv voltage-gated potassium channel support is restored to the axon, but mitochondrial number is
mitochondrion increased over healthy axons. (d) Chronic demyelination causes
swelling of the axon and the accumulation of nonphosphorylated
PP
PP P
PP
PP P PP
PP
phosphorylated neurofilaments neurofilaments. Mitochondria drastically increase in size and
unphosphorylated neurofilaments number to meet higher energetic demands for action potential
propagation
6 DUNCAN ET AL.
nonmyelinating and P0+ myelinating Schwann cells from the peripheral
nervous system (PNS) also form remyelinating Schwann cells within the
CNS (Assinck, Duncan, Plemel, et al., 2017; Ma et al., 2018; Zawadzka
et al., 2010). Interestingly, Schwann cell myelination appears in the spinal
cord as early as 2 weeks postinjury when oligodendrocyte myelin has
only just begun, suggesting a potentially faster response (Duncan, Man-
esh, et al., 2018). Although the mechanism guiding a fate-switch in OPCs
to differentiate into Schwann cells is still not fully understood, Schwann
cells are almost exclusively found where there are fewer astrocytic pro-
cesses. Accordingly, astrocyte-specific deletion of Stat3 decreases
astrogliosis around the lesion and promotes Schwann cell myelination
after chemical demyelination (Monteiro de Castro, Deja, Ma, Zhao, &
Franklin, 2015). This BMP/Wnt rich environment devoid of astrocytes is
permissive for OPCs to adopt a Schwann cell fate, while at the same time
inhibiting them from forming oligodendrocytes (Ulanska-Poutanen et al.,
2018). Schwann cell differentiation from OPCs is therefore dependent on
the injury environment with contusive injuries being very conducive to
damaging astrocytes and producing an environment capable of
supporting considerable Schwann cell myelination.
1.4 | Remyelination after SCI
1.4.1 | Endogenous remyelination is an efficient
regenerative process after experimental SCI
Primary demyelination of axons is seen soon after SCI, but whether
demyelination persists chronically in experimental models has been the
focus of a series of studies, often with contradictory findings depending
on the technique used to measure demyelination (Lasiene, Shupe, Per-
lmutter, & Horner, 2008; Totoiu & Keirstead, 2005). Chronic demyelin-
ation after SCI has been reported in cats and rodents (Blight, 1983b,
1985; Totoiu & Keirstead, 2005) and in some human autopsy samples,
particularly those with residual spinal cord compression (Bunge et al.,
1993; Guest et al., 2005). However, these observations of demyelinated
axons are taken from cross sections at the lesion epicenter and do not dis-
tinguish whether these axons had been transected above or below the
epicenter or whether these axons are spared. Dystrophic tips from trans-
ected axons persist near the lesion (Guest et al., 2005; Kadoya et al.,
2009; Li & Raisman, 1995; Powers et al., 2012), and can spread potassium
channels along their axolemma, consistent with chronic demyelination
(Karimi-Abdolrezaee, Eftekharpour, & Fehlings, 2004; Lasiene et al.,
2008; Powers et al., 2012). Transected corticospinal fibers undergo retro-
grade axonal degeneration (dieback) from the lesion (Pallini, Fernandez, &
Sbriccoli, 1988; Seif, Nomura, & Tator, 2007), where they stabilize several
millimeters away from the lesion in rodent models (Pallini et al., 1988; Seif
et al., 2007; Stirling et al., 2004). These axons are likely unable to contrib-
ute to functional recovery (Guizar-Sahagun et al., 2004; Kadoya et al.,
2009; Silver, Schwab, & Popovich, 2014). Hypothetically,
oligodendrocyte-support of transected axons might alleviate dieback and
improve the chance that axons can undergo regenerative growth, but
myelination has not been explicitly demonstrated to reduce dieback, nor
if such preservation makes transected axons more prone to reforming
functional connections. Instead, the myelin status of spared descending
axons, which may restore conductance to intact circuitry distal to the
lesion, is likely of much more functional relevance. To determine if intact
axons from descending locomotor pathways are demyelinated, tracers
were injected into the red nuclei and motor cortex to trace rubrospinal
and corticospinal axons along their length (Powers et al., 2012). The pres-
ence of punctate Caspr staining, found exclusively at paranodes (Peles
et al., 1997), was used as a surrogate measure of intact myelin (Arancibia-
Carcamo et al., 2017; Etxeberria et al., 2016; Pedraza, Huang, & Colman,
2009). Shorter internodes, characteristic of adult-derived myelin and
remyelination (Young et al., 2013), were found on 53% of rubrospinal
axons in close proximity (±1 mm) to the lesion epicenter suggesting
extensive remyelination of these tracts (Powers et al., 2012). No intact
axons showed evidence of Caspr or potassium channel spreading, typical
of demyelination, and contrasted with transected axons (Powers et al.,
2012). Together, these data indicate that spared axons are not chronically
demyelinated and implies they are instead effectively remyelinated.
Further evidence for efficient remyelination after SCI in rodents
comes from genetic fate mapping approaches, which specifically label
new myelin. Inducing the expression of a membrane-tethered fluores-
cent reporter in OPCs, prior to demyelination, can be used to label de
novo myelination when these OPCs differentiate into oligodendro-
cytes (Kang et al., 2010). This technique can then be used to distin-
guish new myelin from surviving myelin following SCI (Assinck,
Duncan, Plemel, et al., 2017; Duncan, Manesh, et al., 2018; Hesp
et al., 2015; Powers et al., 2013). Doing so reveals persistent and sub-
stantial remyelination by OPC-derived oligodendrocytes and Schwann
cells beginning 3 weeks following SCI and culminating with upward of
28% of the axons at the lesion epicenter being wrapped by new mye-
lin at 12 weeks post-SCI (Assinck, Duncan, Hilton, et al., 2017). These
approaches validate the profound amount of remyelination observed
by measuring internodal length on spared fibers (Powers et al., 2012).
While considerable progress has been made in understanding the
levels of de- and remyelination in experimental SCI, less is known about
what occurs clinically. Humans often have poor remyelination efficiency
in diseases like multiple sclerosis (MS; Goldschmidt, Antel, Konig, Bruck, &
Kuhlmann, 2009; Patrikios et al., 2006; Yeung et al., 2019), and thus it is
plausible that remyelination efficiency might be decreased after SCI rela-
tive to rodents. However, a limited number of pathological studies dem-
onstrate there are relatively few demyelinated axons in most cases
(Guest et al., 2005; Kakulas, 2004; Kakulas & Kaelan, 2015; Norenberg
et al., 2004). The absence of extensive demyelination chronically could be
the result of demyelinated axons being vulnerable to degeneration (Buss
et al., 2004; Nave & Werner, 2014), or as a consequence of efficient
remyelination. Immunohistochemical staining of neurofilaments for axons
and Schwann- and oligodendrocyte-specific myelin markers indicate
remyelination occurs, but that the majority of cases have some level of
acute demyelination within the first year after SCI (Guest et al., 2005;
Kakulas, 2004; Kakulas & Kaelan, 2015), and is more persistent when the
spinal cord is chronically compressed (Bunge et al., 1993). Remyelination
is effective in a spontaneous canine model of SCI (Jeffery et al., 2006),
and in nonhuman primates as long as astrocytes are preserved
(Lachapelle et al., 2005). The presence of demyelinated axons for over a
year after human SCI is in accordance with the relatively slow
DUNCAN ET AL.
OPC-axon interactions
Blocked conductance
in intact axon
Distrophic
endbulb
OPC-derived astrocytes
contribute to the glial scar
F I G U R E 3 Hypothetical functions of oligodendrocyte progenitor cells in the injured CNS beyond remyelination. Schematic of the injured
spinal cord illustrating functions of OPCs beyond generating new oligodendrocytes in response to tissue damage and demyelination. Inlays
highlight the role of OPCs in constraining axon growth, producing astrocytes that contribute to the glial scar, cytokine production, and altering
blood–brain-barrier permeability
proliferative and differentiation rate of human OPCs in both culture and
in vivo relative to rodent OPCs (Ehrlich et al., 2017; Wang et al., 2013;
Windrem et al., 2004). Taken together, there is little evidence from human
samples that the relative extent of chronic demyelination differs dramati-
cally from rodent models and remyelination is observed, albeit the kinet-
ics are likely drastically delayed and could leave axons at risk for
degeneration. That being said, our current knowledge of the extent of
demyelination is based on a very small number of studies and there is still
a great need to understand the frequency of primary demyelination and
effectiveness of remyelination after traumatic CNS injury in humans.
1.4.2 | Spontaneous oligodendrocyte remyelination
does not drive locomotor recovery after SCI
Despite the limited ability of the adult mammalian CNS to regenerate
new connections, spontaneous recovery of motor function can occur
after human SCI as well as in rodents (Curt, Van Hedel, Klaus, Dietz, &
Group, 2008; Hilton et al., 2016; Torres-Espin, Beaudry, Fenrich, &
Fouad, 2018). In rodent models of SCI, the re-establishment of
stepping after thoracic injury has provided a model for understanding
the anatomical and mechanistic basis of spontaneous recovery of
motor function (Basso, Beattie, & Bresnahan, 1995; Courtine et al.,
2008; Filli, Zorner, Weinmann, & Schwab, 2011; Murray et al., 2010;
Rossignol & Frigon, 2011; Schucht, Raineteau, Schwab, & Fouad,
2002). Locomotor recovery is induced, in part, by plasticity in spared
7
Cytokine production
by activated OPC
IL-1β
Ccl2
Csf2
Cxcl1
Cxcl2
IL-6
Inflammatory cells enter
the paranchyma
Endo
Tight junction
alteration
thelia
l ce
Basal lamina
lls
alteration
Macrophage MMP-9
circuitry above and below the site of injury. More specifically, spared
descending input from the brain stem can mediate locomotor recov-
ery or, alternatively, “relay” circuits can form between brain stem neu-
rons and propriospinal neurons to generate the supraspinal input
necessary to induce locomotion (Courtine et al., 2008; Hilton &
Tetzlaff, 2018; Raineteau, Fouad, Bareyre, & Schwab, 2002).
Myelin regeneration is a plausible mechanism to contribute to
these forms of plasticity. Descending axons that are spared by the
injury may be demyelinated and thus require new myelin for effective
conductance or to prevent their degeneration. Similarly, the function-
ality of new circuitry, including between propriospinal neurons and
intraspinal networks mediating locomotion, may require myelination.
Given the extent of remyelination of descending motor axons
after contusive SCI in rodents, we hypothesized that it is a critical
driver of locomotor recovery. We, therefore, blocked OPC differentia-
tion and subsequent remyelination to determine if oligodendrocyte
remyelination is necessary for the recovery of locomotion (Duncan,
Manesh, et al., 2018). The transcription factor Myrf, essential for oligo-
dendrocyte myelin gene expression (Bujalka et al., 2013; Emery et al.,
2009), was deleted from OPCs prior to SCI (Duncan, Manesh, et al.,
2018). Removing Myrf in OPCs does not alter undamaged myelin or
OPC recruitment to the lesion (Duncan et al., 2017). Following contu-
sion SCI, Myrf knockout from OPCs results in a near complete block
of oligodendrocyte remyelination, culminating in chronic demyelin-
ation and 44% fewer axons myelinated at the lesion epicenter
8 DUNCAN ET AL.
(Duncan, Manesh, et al., 2018). Remarkably, spontaneous locomotor
recovery proceeded unencumbered when assessed in an open field
locomotor test (BMS), by gait analysis (Catwalk) or by horizontal lad-
der crossings.
Clearly potential compensatory mechanisms must be further
explored, although we found that preventing oligodendrocyte remyeli-
nation did not spur additional Schwann cell myelination (Duncan, Manesh,
et al., 2018), which seemed confined to injured areas with sparse astrocyte
coverage in the dorsal column of the spinal cord. It is plausible that the rel-
ative extent of demyelination along axons in the rodent contusion model,
which is primarily within 2 mm of the lesion (Powers et al., 2012), is not
sufficient to block conduction. Indeed, axons can conduct through seg-
ments of demyelination of exceeding 2.5 mm in vivo (Felts et al., 1997)
presumably by upregulating and spreading voltage-gated sodium channels
along the axolemma (England et al., 1990, 1991). Additionally, there is a
temporal discordance between oligodendrocyte remyelination and func-
tional recovery. The vast majority of spontaneous locomotor recovery in
mice has already occurred within the first two weeks after injury, prior to
nearly all oligodendrocyte remyelination (Duncan, Manesh, et al., 2018).
Overall, we found that OPCs are a critical source of remyelinating oligo-
dendrocytes, and that preventing OPC differentiation results in sustained
demyelination. To our surprise, we found that endogenous oligodendro-
cyte remyelination of spared axons is not a key contributor to spontane-
ous locomotor recovery following contusive SCI.
1.4.3 | Is Schwann cell myelination linked to
functional recovery?
Schwann cell myelination is observed within the spinal cord following
experimental contusive SCI, can restore conductance to CNS axons
(Felts & Smith, 1987; Honmou, Felts, Waxman, & Kocsis, 1996) and could
be a mediator of recovery. The deletion of Neuregulin-1 (Nrg-1), which is
instructive for Schwann cell myelination (Michailov et al., 2004), could be
used to determine its role in locomotor recovery after SCI. Indeed, Bartus
et al. (2016) found the inducible deletion of Nrg-1 is associated with
impaired functional locomotor recovery after SCI. One limitation of this
approach is that the tamoxifen inducible Cre mice (CAG Cre-ERT2) used
have expression in virtually every cell type (Hayashi & McMahon, 2002),
and therefore loss of NRG-1 may affect locomotor recovery by mecha-
nisms other than by inhibiting Schwann cell myelination. NRG-1 signaling
promotes oligodendrocyte differentiation (Gauthier, Kosciuczyk,
Tapley, & Karimi-Abdolrezaee, 2013; Kataria et al., 2018), regulates
astrogliosis (Alizadeh et al., 2017; Gauthier et al., 2013) and alters inflam-
mation by reducing the expression of key inflammatory cytokines after
SCI (Alizadeh et al., 2017; Alizadeh, Santhosh, Kataria, Gounni, & Karimi-
Abdolrezaee, 2018; Gauthier et al., 2013). Additionally, the deletion of
just the NRG-1 Type I and II isotypes—which are dispensable for Schwann
cell myelination—is sufficient to inhibit open field locomotion (Bartus
et al., 2016). To address these concerns, Bartus et al. (2019) knocked out
the ErbB3/4 receptors from PDGFRα+ cells following SCI and similarly
observed impaired Schwann cell myelination from endogenous OPCs,
with no reported effect on oligodendrocyte remyelination. Functionally,
the deletion of ErbB3/4 results in deficits on an inclined beam walking
test, but has no effect on gross open field locomotion (Basso mouse
score), like previously reported with the Nrg1 deletion (Bartus et al., 2016;
Bartus et al., 2019). However, glial scarring, axon growth, and inflamma-
tion were not examined, all of which are impacted by Nrg1-ErbB signal-
ing. It also remains unclear why inhibiting the remyelination of a relatively
low number of sensory axons in the dorsal column by Schwann cells
would impair motor recovery after contusive SCI when a much larger
number of demyelinated axons in the ventrolateral columns after oligo-
dendrocyte ablation does not (Duncan, Manesh, et al., 2018). Neverthe-
less, these studies point to a role of NRG-1-ErbB3/4 in OPC-derived
Schwann cell differentiation and locomotor recovery, though given the
multifaceted nature of Neuregulin signaling and Schwann cells in repair,
the precise mechanism(s) by which it confers functional benefits remains
unclear.
1.4.4 | Does the acceleration of remyelination
constitute a therapeutic target for SCI?
Endogenous OPCs differentiate into oligodendrocytes that regenerate
myelin around the majority of spared demyelinated axons following
experimental SCI, but remyelination is notably delayed relative to toxin
models of demyelination. Remyelination commences within a week fol-
lowing lysolecithin demyelination (Jeffery & Blakemore, 1995), whereas
oligodendrocyte remyelination is scant until at least the third week after
SCI (Assinck, Duncan, Plemel, et al., 2017; Duncan, Manesh, et al., 2018;
James et al., 2011). The speed of remyelination following SCI is likely
affected by injury-induced changes in the microenvironment, which have
been recently reviewed elsewhere (Alizadeh & Karimi-Abdolrezaee,
2016; Plemel et al., 2014; Pu, Stephenson, & Yong, 2018; Pukos, Goodus,
Sahinkaya, & McTigue, 2019). Notably, remyelination may be slowed by
cytotoxicity near the lesion, insufficient tissue oxygenation (Tsai et al.,
2016; Yuen et al., 2014), or inhibitory factors in the glial scar and myelin
debris (Buss & Schwab, 2003; Church, Milich, Lerch, Popovich, &
McTigue, 2017; Dyck et al., 2018; Dyck, Kataria, Akbari-Kelachayeh, Sil-
ver, & Karimi-Abdolrezaee, 2019; Keough et al., 2016; Plemel, Manesh,
Sparling, & Tetzlaff, 2013). Accelerated remyelination is sufficient to pre-
serve axons following T-cell mediated demyelination (Mei et al., 2016).
Rapid remyelination may restore metabolic support of the axon to the oli-
godendrocyte (Philips & Rothstein, 2017; Saab & Nave, 2017), protect
against inflammatory mediators like nitric oxide (Redford et al., 1997), and
calcium accumulation within the axon (Witte et al., 2019). It is therefore
possible that demyelinated axons after SCI may be more vulnerable to
loss given the relatively sluggish remyelination. However, following SCI
primary demyelination is confined to the proximity of the lesion epicenter
(Powers et al., 2012), and no study has directly ascertained if the loss of
only a small number of myelin sheaths along the length of an axon leaves
an axon sufficiently metabolically compromised to be vulnerable to sub-
sequent loss. Still, if hastened remyelination is successful at preserving
axons it may be a viable therapeutic target for SCI (Plemel et al., 2014).
Given the longer timeframe necessary for OPC differentiation in humans
relative to rodents (Goldman & Kuypers, 2015; Windrem et al., 2004),
accelerating remyelination may be helpful clinically as axons may be
stressed longer in humans than in experimental rodent models.
DUNCAN ET AL.
Two strategies have been used to speed remyelination: (a) the
transplantation of exogenous cells to directly remyelinate, or less fre-
quently, (b) enhancing endogenous precursor-derived remyelination.
The following section will examine the efficacy of these strategies to
promote remyelination, the evidence of whether this increases axo-
n/tissue sparing and its relationship to improvements in functional
recovery.
1.4.5 | Cellular transplantation to accelerate
remyelination
The transplantation of cells into the injured spinal cord with the aim of
producing new oligodendrocytes or Schwann cells has been frequently
pursued to improve remyelination, and is the topic of several thorough
reviews (Assinck, Duncan, Hilton, et al., 2017; Kanno, Pearse, Ozawa,
Itoi, & Bunge, 2015; Myers et al., 2016). Transplanted cells will be in com-
petition with endogenous OPC-derived remyelinating cells, which are
capable of efficient, if somewhat delayed, remyelination. Transplanted
cells, therefore, only have a limited time window of efficacy that is
supported by the preponderance of studies: myelinating cell transplants
can improve remyelination, white matter content, and function when
transplanted within the first several weeks after injury (Biernaskie et al.,
2007; Cao et al., 2010; Karimi-Abdolrezaee, Eftekharpour, Wang,
Morshead, & Fehlings, 2006; Keirstead et al., 2005; Pearse et al., 2004).
While more chronic transplantations of remyelinating cells have in some
cases shown to be beneficial in increasing locomotor recovery (Barakat
et al., 2005; Karimi-Abdolrezaee, Eftekharpour, Wang, Schut, & Fehlings,
2010; Nori et al., 2018; Okubo et al., 2018), none of these chronic studies
demonstrate that the extent of remyelination is improved using gold-
standard measurements of electron microscopy or fluorescently-labelled
new myelin. Therefore, myelinating cell transplants likely need to be
transplanted early after SCI to outcompete endogenous progenitors and
accelerate remyelination.
It is also possible that benefits following myelinating cell transplanta-
tion are conferred by mechanisms other than remyelination (Assinck,
Duncan, Hilton, et al., 2017). Transplanted neural progenitor cells (NPCs)
and glial progenitors differentiate into many cell types following SCI, all of
which may influence repair (Tetzlaff et al., 2011). To determine if the ben-
eficial effect is incurred by more rapid remyelination, transplantation of
NPCs from shiverer mice, which lack compact myelin (Dupouey et al.,
1979; Kirschner & Ganser, 1980), were compared to transplanted myelin-
competent NPCs (Hawryluk et al., 2014; Yasuda et al., 2011). They found
that locomotor improvements were abolished when transplanted cells
were rendered unable to myelinate (Hawryluk et al., 2014; Yasuda et al.,
2011) supporting a role of myelinogenesis by transplanted cells in driving
improved recovery. Likewise, transplantations with enhanced oligoden-
drocyte differentiation over naïve NPCs have been associated with
improved myelination and locomotor function, indicating forming oligo-
dendrocyte lineage cells may be particularly advantageous (Cao et al.,
2010; Hofstetter et al., 2005; Hwang et al., 2009; Piltti et al., 2017).
Whether transplanted oligodendrocytes enhance spared white matter via
direct trophic support of axons remains uncertain. Transplanted cells may
also spur endogenous cell remyelination (Biernaskie et al., 2007), which
9
may be causal in locomotor improvements. It will be critical to determine
which cell types elicit recovery, and the mechanisms by which these cells
drive recovery in order to optimize them for use in the clinic.
1.5 | Manipulation of endogenous oligodendrocyte
lineage cells to accelerate remyelination
OPCs are the most proliferative cell population and the primary source of
new oligodendrocytes after SCI (Barnabe-Heider et al., 2010; Duncan,
Manesh, et al., 2018). These attributes make OPCs an ideal cell population
to target to enhance their differentiation into new oligodendrocytes to
accelerate remyelination. Approaches that have improved endogenous
OPC differentiation after SCI include attenuating inhibitors of OPC differ-
entiation like BMP signaling (Sellers et al., 2009; Wang et al., 2011) or
myelin debris (Church et al., 2017; Plemel et al., 2013). Alternatively,
expressing known promoters of oligodendrocyte differentiation like T3
(Shultz, Wang, Nong, Zhang, & Zhong, 2017), or growth factors like NT-3,
BDNF (McTigue, Horner, Stokes, & Gage, 1998) have also been success-
ful in promoting OPC differentiation into new oligodendrocytes. None of
these experiments examined axon sparing or functional recovery in the
context of more rapid oligodendrocyte differentiation, but a series of
experiments increasing Nrg1 signaling have done so (Alizadeh et al.,
2017; Gauthier et al., 2013; Whittaker et al., 2012). Administration of
recombinant Nrg1-β1, promotes remyelination in a chemical model of
demyelination (Kataria et al., 2018), increases white matter sparing, and
improves open field locomotion following SCI (Alizadeh et al., 2017;
Gauthier et al., 2013). However, Nrg1-β1 also alters the inflammatory
milieu and reduces glial scaring (Alizadeh et al., 2018), making it difficult to
ascertain if remyelination is driving these functional benefits. Application
of Nrg1-β3 (GGF2) following SCI increases oligodendrocyte differentia-
tion and the quality of stepping in rats and mice (Whittaker et al., 2012).
In rats, Nrg1-β3 administration does not alter spared white matter at
7 days postinjury but increases it by 42 days post-SCI (Whittaker et al.,
2012). This delay in white matter sparing suggests that Nrg1-β3 does not
drastically alter early secondary damage to myelinated axons, but may be
reflective of improved regenerative processes, such as remyelination, by
42 days postinjury. Collectively, these studies are a proof of principle that
speeding endogenous oligodendrocyte differentiation is possible after
SCI and has in some cases been associated with improved white matter
volume and functional benefits. However, further cell-specific manipula-
tions will be needed to determine if locomotor recovery is being derived
by remyelination or other factors.
1.6 | Beyond Remyelination: Alternative functions of
oligodendrocyte lineage cells after SCI
Local tissue damage, including that caused by mechanical injury, results in
the activation of glial cells, which produce a barrier or scar to segregate
inflammatory cells to areas of tissue damage and protect residual tissue
(Burda & Sofroniew, 2014; Faulkner et al., 2004; Silver et al., 2014;
Sofroniew, 2015). The scar contains numerous cell types, prominently
astrocytes fibroblasts, but also OPCs (Busch et al., 2010; Cregg et al.,
2014; Silver et al., 2014). Recent evidence indicates that OPCs local to
10
the scar may be major regulators of tissue repair, extending their func-
tions beyond generating new oligodendrocytes for remyelination
(Fernandez-Castaneda & Gaultier, 2016; Hamanaka, Ohtomo, Takase,
Lok, & Arai, 2018; Silver et al., 2014). The following sections will discuss
potential functions of OPCs in CNS injury focusing on their roles in regu-
lating axonal growth and the immune response to injury.
1.6.1 | OPCs contribute to scarring and may regulate
axonal growth
OPCs, often identified by the expression of NG2 (Nishiyama et al., 1996),
proliferate near the lesion in response to SCI (Horky, Galimi, Gage, &
Horner, 2006; McTigue et al., 2001; Tripathi & McTigue, 2007; Zai &
Wrathall, 2005) and contribute to the scar (Filous et al., 2014) (Figure 3).
This leaves OPCs in the ideal location to regulate axon growth and die-
back, potentially through the expression of extracellular proteins. Extra-
cellular molecules like chondroitin sulfate proteoglycans (CSPG)s inhibit
axon regeneration (Cregg et al., 2014; Siebert, Conta Steencken, &
Osterhout, 2014). Dystrophic axons, which persist near the lesion epicen-
ter after SCI (Kadoya et al., 2009; Li & Raisman, 1995; Powers et al.,
2012), are often associated with cells expressing the CSPG NG2 (Busch
et al., 2010; Tan, Colletti, Rorai, Skene, & Levine, 2006). Function blocking
NG2 antibodies (Tan et al., 2006), as well as the depletion of proliferative
NG2 cells (Hesp et al., 2018), increase axon growth following SCI,
supporting a role for NG2 in constraining axon regeneration. However, in
apparent contrast to a function of NG2+ cells in reducing axon growth,
NG2 gene ablation decreases the number of serotonergic axons within
the lesion (de Castro Jr, Tajrishi, Claros, & Stallcup, 2005). One possibility
to rectify these findings is that NG2+ cells also prevent axonal dieback by
associating with dystrophic axons, which is supported by greater sensory
axon dieback in NG2 knockout mice, and the capacity of OPCs to stabilize
axons endbulbs in vitro (Busch et al., 2010). These data suggest a model in
which axon dieback is mitigated by NG2+ cells following SCI, but then
NG2+ cells subsequently entrap growth cones and diminish axon growth
(Silver et al., 2014; Son, 2015).
Likewise, NG2+ cells may impair regeneration of peripheral dorsal
root ganglion (DRG) axons into the spinal cord. Crushing peripheral roots
has been traditionally used as a model to understand the intrinsic inhibi-
tory environment of the CNS on axon growth, as DRG axons tend to stall
at the PNS/CNS boundary (Di Maio et al., 2011; Hanna, Son, & Dempsey,
2011; Ramer, Priestley, & McMahon, 2000; Son, 2015). Reports from the
1980's suggested that these immobilized axons can form “axo-glial
terminals,” which resemble presynapses apposed from glial processes,
which were thought to be astrocytes (Carlstedt, 1985; Liuzzi & Lasek,
1987). However, by using wholemount immunostaining of the DRG and
spinal cord following a dorsal root crush, it was shown that DRG axons
are often immobilized on NG2+ processes rather than GFAP+ astrocytes
or myelin (Di Maio et al., 2011; Hanna et al., 2011; Son, 2015). Ultrastruc-
tural examination confirmed that DRG axons have vesicle accumulation
resembling an active zone proximal to glial processes, though these glial
processes were not explicitly identified to be NG2+ by immunoelectron
microscopy. Genetic knockout or antibody-mediated blocking of NG2
proteoglycan will be needed to confirm if NG2 cells are causative in
DUNCAN ET AL.
preventing DRG regeneration following crush. Collectively, NG2+ cells
are associated with entrapped growth cones from both damaged CNS or
PNS axons growing into the CNS parenchyma, and may be serving to
entrap and diminish axon growth.
NG2 is often used to identify OPCs in uninjured tissue (Nishiyama
et al., 1996) and is also strongly expressed by OPCs after SCI (McTigue
et al., 2001). It should be cautioned that other cells including blood-
derived macrophages express NG2 near the lesion (McTigue, Tripathi, &
Wei, 2006), so it remains unclear whether these entrapping cells in vivo
are in fact oligodendrocyte lineage cells. The NG2+ cells associated with
entrapped axons express both vimentin and nestin (Filous et al., 2014).
These are progenitor markers not typically associated with adult OPCs
(Barnabe-Heider et al., 2010; Zhang et al., 2014), and are only expressed
transiently in OPCs following dissociation for cell culture (Behar,
McMorris, Novotny, Barker, & Dubois-Dalcq, 1988; Tang, Tokumoto, &
Raff, 2000).Whether activated OPCs have adapted a more progenitor-
like phenotype in vivo in response to injury (Moyon et al., 2015) or if these
NG2-expressing cells are derived from other cell types remains unclear.
Future studies will need to specifically determine if axon-entrapping NG2
+ cells are derived from the oligodendrocyte lineage by genetically label-
ing OPCs prior to injury.
Scar formation has beneficial aspects: it constrains blood-derived leu-
kocytes and protects tissue from additional damage (Faulkner et al., 2004;
Goritz et al., 2011; Herrmann et al., 2008; Sabelstrom et al., 2013). How-
ever, parenchymal astrocytes are limited in their capacity to migrate and
proliferate (Barnabe-Heider et al., 2010; Tsai et al., 2012). In cases of sub-
stantial tissue disruption, OPCs could be an additional source of astro-
cytes to further supplement their numbers. There has been some debate
about the capacity of OPCs to differentiate into astrocytes following SCI,
but two groups have recently provided compelling evidence they do so
using genetic fate mapping approaches (Hackett et al., 2016; Huang et al.,
2018). Attenuating the OPC response to injury also diminishes
astrogliosis, suggesting a correlative relationship between these pro-
cesses (Hesp et al., 2018; Rodriguez et al., 2014). For example, inhibiting
NG2+ cell proliferation by using mice expressing thymidine kinase in NG2
+ cells and treating these mice with ganciclovir (GCV), results in discontin-
uous expression of GFAP around the lesion, worsened edema, and
impaired recovery after SCI (Hesp et al., 2018). Likewise, inhibition of
OPC proliferation by inducible knockout of β-catenin from OPCs reduces
GFAP expression around the lesion (Rodriguez et al., 2014). Interestingly,
in both approaches (Tk/GCV or β-catenin knockout) increased axon num-
ber was observed within the scar. Collectively, these data suggest that
OPCs are critical for the appropriate scar formation, reducing edema, and
provide further support that NG2 cells or their progeny restrict axon
growth. However, it is still unclear if OPCs are acting directly, or simply
altering astrocyte function. Likewise, current conditional and inducible
Cre lines (e.g., PDGFRα CreERT and NG2 CreERT) used to manipulate
gene expression in OPCs share expression of these genes with
vasculature-associated cells including pericytes (Assinck, Duncan, Plemel,
et al., 2017; Kang et al., 2010). Pericytes contribute to the accumulation
of fibrotic stromal cells within the scar, which inhibits corticospinal axon
growth (Dias et al., 2018). Caution is therefore necessary when inter-
preting these studies as an OPC-specific effect. However, the
DUNCAN ET AL.
accumulation of OPCs at the lesion, their capacity to differentiate into
astrocytes, their prominent expression of NG2, and the functional studies
where their proliferation is inhibited paint a cumulative picture that these
cells are likely crucial for the scarring response and regulate axon growth.
1.6.2 | OPCs rapidly respond to tissue injury and
may regulate the subsequent immune response
Live-imaging studies have determined that OPCs can elongate pro-
cesses toward tissue injury within hours and begin proliferating rap-
idly thereafter (Hill et al., 2014; Hughes et al., 2013). While not as
rapid as local microglial responses to tissue damage (Davalos et al.,
2005), OPCs respond quickly to damage. Several new studies provide
compelling evidence that this quick response to demyelination helps
regulate both adaptive and innate immune responses (Figure 3).
OPCs regulate adaptive immune responses by acting as antigen pre-
senting cells during chemical and autoimmune-mediated demyelination
(Falcao et al., 2018; Kirby et al., 2018). In vivo gene profiling confirms that
oligodendrocyte-lineage cells express the major histocompatibility com-
plex Genes I and II in response to cytokines like IFNγ (Falcao et al., 2018;
Kirby et al., 2018). Additionally, OPCs phagocytose antigens in reaction
to IFNγ stimulation, and subsequently present these antigens to CD4+ T-
helper cells to support their survival and proliferation (Falcao et al., 2018).
OPCs also present antigens to activate CD8+ cytotoxic T-cells (Kirby
et al., 2018). Interestingly, transfer of IFNγ-expressing astrocytes or effec-
tor T-cells results in impaired differentiation of OPCs into oligodendro-
cytes and slowed remyelination (Kirby et al., 2018). These data indicate
that OPCs are co-opted by the immune system to be involved in antigen
presentation serving as an intermediate to drive further immune
responses at the cost of their capacity to generate new oligodendrocytes.
OPCs are thus influenced by their local environment during tissue dam-
age and can encourage subsequent adaptive immune responses.
OPCs also produce cytokines to regulate the innate immune response
following tissue damage (Figure 3). For example, during autoimmune
demyelination, the deletion of the key transducer of IL-17 signaling, Act1,
in OPCs and pericytes reduces expression of inflammatory cytokines, leu-
kocyte infiltration, and clinical scores (Kang et al., 2013). OPCs alter their
transcriptome in response to demyelination and prominently express the
inflammatory cytokines IL1β and CCL2 (Moyon et al., 2015), a potent reg-
ulator of monocyte infiltration (Deshmane, Kremlev, Amini, & Sawaya,
2009). Following ischemia (Seo et al., 2013), or demyelination (Pham
et al., 2012), OPCs may regulate BBB permeability by rapidly expressing
MMP9, which is associated with weakening of the BBB, and subsequent
immune infiltration (Hamanaka et al., 2018; Rempe, Hartz, & Bauer,
2016). Indeed, conditioned media from OPCs reduces the expression of
tight junction proteins in endothelial cells, which may permit increased
leukocyte infiltration (Seo et al., 2013). In traumatic SCI, inhibiting OPC
proliferation via the inducible knockout of β-catenin reduces the number
of microglia/macrophages within the lesion, suggesting a role of OPCs in
potentiating the innate immune response after SCI (Rodriguez et al.,
2014). As before, given that the knockout would also affect pericytes, it
remains unclear whether this phenotype is derived from diminishing the
OPC or pericyte responses to injury (Duncan, Assinck, & Hilton, 2014;
11
Hesp et al., 2018). Given the rapid proliferation of OPCs and presence
within the scar where they could affect immune infiltration and lesion
development, it will be crucial to determine to what extent they sculpt
the inflammatory response after SCI.
2 | C O N CL U S I O N
OPCs are the largest source of endogenous progenitors in the adult spinal
cord. Following traumatic injury, OPCs become multipotent contributing
to the replacement of lost oligodendrocytes and astrocytes (Assinck,
Duncan, Plemel, et al., 2017; Hackett et al., 2018). OPCs produce virtually
all new remyelinating oligodendrocytes and the majority of myelinating
Schwann cells (Assinck, Duncan, Plemel, et al., 2017; Barnabe-Heider
et al., 2010), which together are effective in remyelinating nearly all intact
demyelinated axons following experimental SCI in rodents (Duncan, Man-
esh, et al., 2018; Lasiene et al., 2008; Powers et al., 2012). While
remyelination is sufficient to improve conductance along axons (Smith,
Blakemore, & Mcdonald, 1979) and may help preserve axons over the
long-term (Lee et al., 2012), spontaneous oligodendrocyte remyelination
is not a major driver of the limited locomotor recovery observed early
after contusive SCI (Duncan, Manesh, et al., 2018). However,
remyelination is somewhat delayed in the rodent spinal cord relative to
chemical demyelination, and remyelinating cell transplants and strategies
to improve endogenous remyelination has been shown to facilitate loco-
motor recovery, especially when instituted shortly after SCI, though it
remains unclear precisely how these interventions are driving recovery
(Assinck, Duncan, Hilton, et al., 2017). Given the multifaceted nature of
the OPC responses to traumatic injury, it is plausible that OPCs have roles
in repair not related to the generation of new myelinating cells. Accord-
ingly, the inhibition of OPC proliferation in response to SCI impairs recov-
ery, without affecting oligodendrocyte density (Hesp et al., 2018). OPCs
contribute to the glial scar and through their expression of the NG2 pro-
teoglycan may regulate axonal growth and dieback (Filous et al., 2014;
Hackett et al., 2018). They may also regulate inflammatory responses
after SCI and are capable of antigen presentation and cytokine production
(Falcao et al., 2018; Kang et al., 2013; Moyon et al., 2015). These potential
novel functions of OPCs in tissue remodeling after injury could be critical
mediators of functional recovery and may provide new therapeutic ave-
nues to promote recovery.
ACKNOWLEDG MENTS
The authors would like to thank the generous support from the Canadian
Institute of Health Research and the Multiple Sclerosis Society of Canada
to W.T. We also thank all current and past members of the Tetzlaff labo-
ratory for their thought-provoking discussion on myelin regeneration and
drivers of locomotor recovery following SCI. G.J.D. is supported by a
National Multiple Sclerosis Society fellowship (FG-1808-32238). B.J.H. is
supported by a Wings for Life (WfL) Aguayo-Tator Mentoring Fellowship
and a nonstipendiary European Molecular Biology Organization (EMBO)
Long-Term Fellowship (ALTF 28-2017). P.A. is supported by an Multiple
Sclerosis Society of Canada Postdoctoral Fellowship and Marie Curie
12
(MSCA) Individual Fellowship. W.T. holds the John and Penny Ryan Brit-
ish Columbia Leadership Chair in Spinal Cord Research.
CONF LICT OF IN TE RE ST
Authors have no conflict of interest to report.
ORCID
Brett J. Hilton https://orcid.org/0000-0003-2813-2294
Jason R. Plemel https://orcid.org/0000-0003-1385-1464
Wolfram Tetzlaff https://orcid.org/0000-0003-3462-1676
RE FE R ENC E S
Alizadeh, A., Dyck, S. M., & Karimi-Abdolrezaee, S. (2015). Myelin damage
and repair in pathologic CNS: Challenges and prospects. Frontiers in
Molecular Neuroscience, 8, 35. https://doi.org/10.3389/fnmol.2015.
00035
Alizadeh, A., Dyck, S. M., Kataria, H., Shahriary, G. M., Nguyen, D. H.,
Santhosh, K. T., & Karimi-Abdolrezaee, S. (2017). Neuregulin-1 posi-
tively modulates glial response and improves neurological recovery
following traumatic spinal cord injury. Glia, 65(7), 1152–1175. https://
doi.org/10.1002/glia.23150
Alizadeh, A., & Karimi-Abdolrezaee, S. (2016). Microenvironmental regula-
tion of oligodendrocyte replacement and remyelination in spinal cord
injury. The Journal of Physiology, 594(13), 3539–3552. https://doi.org/
10.1113/JP270895
Alizadeh, A., Santhosh, K. T., Kataria, H., Gounni, A. S., & Karimi-
Abdolrezaee, S. (2018). Neuregulin-1 elicits a regulatory immune response
following traumatic spinal cord injury. Journal of Neuroinflammation, 15(1),
53. https://doi.org/10.1186/s12974-018-1093-9
Almeida, R. G., & Lyons, D. A. (2014). On the resemblance of synapse for-
mation and CNS myelination. Neuroscience, 276, 98–108. https://doi.
org/10.1016/j.neuroscience.2013.08.062
Arancibia-Carcamo, I. L., Ford, M. C., Cossell, L., Ishida, K., Tohyama, K., &
Attwell, D. (2017). Node of Ranvier length as a potential regulator of
myelinated axon conduction speed. eLife, 6, 6. https://doi.org/10.
7554/eLife.23329
Assinck, P., Duncan, G. J., Hilton, B. J., Plemel, J. R., & Tetzlaff, W. (2017).
Cell transplantation therapy for spinal cord injury. Nature Neuroscience,
20(5), 637–647. https://doi.org/10.1038/nn.4541
Assinck, P., Duncan, G. J., Plemel, J. R., Lee, M. J., Stratton, J. S.,
Manesh, S. B., … Tetzlaff, W. (2017). Myelinogenic plasticity of oligo-
dendrocyte precursor cells following spinal cord contusion injury. The
Journal of Neuroscience, 37, 8635–8654. https://doi.org/10.1523/
JNEUROSCI.2409-16.2017
Atkinson, P. P., & Atkinson, J. L. (1996). Spinal shock. Mayo Clinic Proceedings,
71(4), 384–389. https://doi.org/10.1016/S0025-6196(11)64067-6
Barakat, D. J., Gaglani, S. M., Neravetla, S. R., Sanchez, A. R.,
Andrade, C. M., Pressman, Y., … Pearse, D. D. (2005). Survival, integra-
tion, and axon growth support of glia transplanted into the chronically
contused spinal cord. Cell Transplantation, 14(4), 225–240. https://doi.
org/10.3727/000000005783983106
Barnabe-Heider, F., Goritz, C., Sabelstrom, H., Takebayashi, H.,
Pfrieger, F. W., Meletis, K., & Frisen, J. (2010). Origin of new glial cells
in intact and injured adult spinal cord. Cell Stem Cell, 7(4), 470–482.
https://doi.org/10.1016/j.stem.2010.07.014
Bartus, K., Burnside, E. R., Galino, J., James, N. D., Bennett, D. L. H., &
Bradbury, E. J. (2019). ErbB receptor signaling directly controls oligo-
dendrocyte progenitor cell transformation and spontaneous
DUNCAN ET AL.
remyelination after spinal cord injury. Glia, 67, 1036–1046. https://
doi.org/10.1002/glia.23586
Bartus, K., Galino, J., James, N. D., Hernandez-Miranda, L. R., Dawes, J. M.,
Fricker, F. R., … Bradbury, E. J. (2016). Neuregulin-1 controls an
endogenous repair mechanism after spinal cord injury. Brain, 139(Pt 5),
1394–1416. https://doi.org/10.1093/brain/aww039
Basso, D. M., Beattie, M. S., & Bresnahan, J. C. (1995). A sensitive and reli-
able locomotor rating scale for open field testing in rats. Journal of
Neurotrauma, 12(1), 1–21. https://doi.org/10.1089/neu.1995.12.1
Beaumont, E., Onifer, S. M., Reed, W. R., & Magnuson, D. S. (2006). Mag-
netically evoked inter-enlargement response: An assessment of
ascending propriospinal fibers following spinal cord injury. Experimen-
tal Neurology, 201(2), 428–440. https://doi.org/10.1016/j.expneurol.
2006.04.032
Behar, T., McMorris, F. A., Novotny, E. A., Barker, J. L., & Dubois-Dalcq, M.
(1988). Growth and differentiation properties of O-2A progenitors
purified from rat cerebral hemispheres. Journal of Neuroscience
Research, 21(2–4), 168–180. https://doi.org/10.1002/jnr.490210209
Bergles, D. E., Jabs, R., & Steinhauser, C. (2010). Neuron-glia synapses in
the brain. Brain Research Reviews, 63(1–2), 130–137. https://doi.org/
10.1016/j.brainresrev.2009.12.003
Bergles, D. E., Roberts, J. D., Somogyi, P., & Jahr, C. E. (2000). Glutamatergic
synapses on oligodendrocyte precursor cells in the hippocampus. Nature,
405(6783), 187–191. https://doi.org/10.1038/35012083
Bernardi, P. (1992). Modulation of the mitochondrial cyclosporin A-
sensitive permeability transition pore by the proton electrochemical
gradient. Evidence that the pore can be opened by membrane depolar-
ization. The Journal of Biological Chemistry, 267(13), 8834–8839.
Biernaskie, J., Sparling, J. S., Liu, J., Shannon, C. P., Plemel, J. R., Xie, Y., …
Tetzlaff, W. (2007). Skin-derived precursors generate myelinating
Schwann cells that promote remyelination and functional recovery
after contusion spinal cord injury. Journal of Neuroscience, 27(36),
9545–9559. https://doi.org/10.1523/Jneurosci.1930-07.2007
Blight, A. R. (1983a). Axonal physiology of chronic spinal cord injury in the
cat: Intracellular recording in vitro. Neuroscience, 10(4), 1471–1486.
Blight, A. R. (1983b). Cellular morphology of chronic spinal cord injury in
the cat: Analysis of myelinated axons by line-sampling. Neuroscience,
10(2), 521–543.
Blight, A. R. (1985). Delayed demyelination and macrophage invasion: A
candidate for secondary cell damage in spinal cord injury. Central Ner-
vous System Trauma, 2(4), 299–315. https://doi.org/10.1089/cns.
1985.2.299
Bujalka, H., Koenning, M., Jackson, S., Perreau, V. M., Pope, B., Hay, C. M.,
… Emery, B. (2013). MYRF is a membrane-associated transcription fac-
tor that autoproteolytically cleaves to directly activate myelin genes.
PLoS Biology, 11(8), e1001625. https://doi.org/10.1371/journal.pbio.
1001625
Bunge, R. P., Puckett, W. R., Becerra, J. L., Marcillo, A., & Quencer, R. M.
(1993). Observations on the pathology of human spinal cord injury. A
review and classification of 22 new cases with details from a case of
chronic cord compression with extensive focal demyelination.
Advances in Neurology, 59, 75–89.
Burda, J. E., & Sofroniew, M. V. (2014). Reactive gliosis and the mul-
ticellular response to CNS damage and disease. Neuron, 81(2),
229–248. https://doi.org/10.1016/j.neuron.2013.12.034
Busch, S. A., Horn, K. P., Cuascut, F. X., Hawthorne, A. L., Bai, L. H.,
Miller, R. H., & Silver, J. (2010). Adult NG2+cells are permissive to neu-
rite outgrowth and stabilize sensory axons during macrophage-
induced axonal dieback after spinal cord injury. Journal of Neuroscience,
30(1), 255–265. https://doi.org/10.1523/Jneurosci.3705-09.2010
Buss, A., Brook, G. A., Kakulas, B., Martin, D., Franzen, R., Schoenen, J., …
Schmitt, A. B. (2004). Gradual loss of myelin and formation of an astro-
cytic scar during Wallerian degeneration in the human spinal cord.
Brain, 127(Pt 1), 34–44. https://doi.org/10.1093/brain/awh001
DUNCAN ET AL.
Buss, A., & Schwab, M. E. (2003). Sequential loss of myelin proteins during
Wallerian degeneration in the rat spinal cord. Glia, 42(4), 424–432.
https://doi.org/10.1002/glia.10220
Cai, J., Qi, Y., Hu, X., Tan, M., Liu, Z., Zhang, J., … Qiu, M. (2005). Genera-
tion of oligodendrocyte precursor cells from mouse dorsal spinal cord
independent of Nkx6 regulation and Shh signaling. Neuron, 45(1),
41–53. https://doi.org/10.1016/j.neuron.2004.12.028
Campbell, G. R., Worrall, J. T., & Mahad, D. J. (2014). The central role of mito-
chondria in axonal degeneration in multiple sclerosis. Multiple Sclerosis, 20
(14), 1806–1813. https://doi.org/10.1177/1352458514544537
Cao, Q., He, Q., Wang, Y., Cheng, X., Howard, R. M., Zhang, Y., …
Whittemore, S. R. (2010). Transplantation of ciliary neurotrophic
factor-expressing adult oligodendrocyte precursor cells promotes
remyelination and functional recovery after spinal cord injury. The
Journal of Neuroscience, 30(8), 2989–3001. https://doi.org/10.1523/
JNEUROSCI.3174-09.2010
Carlstedt, T. (1985). Regenerating axons form nerve terminals at astro-
cytes. Brain Research, 347(1), 188–191.
Church, J. S., Milich, L. M., Lerch, J. K., Popovich, P. G., & McTigue, D. M.
(2017). E6020, a synthetic TLR4 agonist, accelerates myelin debris
clearance, Schwann cell infiltration, and remyelination in the rat spinal
cord. Glia, 65(6), 883–899. https://doi.org/10.1002/glia.23132
Courtine, G., Song, B., Roy, R. R., Zhong, H., Herrmann, J. E., Ao, Y., …
Sofroniew, M. V. (2008). Recovery of supraspinal control of stepping
via indirect propriospinal relay connections after spinal cord injury.
Nature Medicine, 14(1), 69–74. https://doi.org/10.1038/nm1682
Craner, M. J., Newcombe, J., Black, J. A., Hartle, C., Cuzner, M. L., &
Waxman, S. G. (2004). Molecular changes in neurons in multiple scle-
rosis: Altered axonal expression of Nav1.2 and Nav1.6 sodium chan-
nels and Na+/Ca2+ exchanger. Proceedings of the National Academy of
Sciences of the United States of America, 101(21), 8168–8173. https://
doi.org/10.1073/pnas.0402765101
Cregg, J. M., DePaul, M. A., Filous, A. R., Lang, B. T., Tran, A., & Silver, J.
(2014). Functional regeneration beyond the glial scar. Experimental
Neurology, 253, 197–207. https://doi.org/10.1016/j.expneurol.2013.
12.024
Criste, G., Trapp, B., & Dutta, R. (2014). Axonal loss in multiple sclerosis:
Causes and mechanisms. Handbook of Clinical Neurology, 122,
101–113. https://doi.org/10.1016/B978-0-444-52001-2.00005-4
Crowe, M. J., Bresnahan, J. C., Shuman, S. L., Masters, J. N., &
Beattie, M. S. (1997). Apoptosis and delayed degeneration after spinal
cord injury in rats and monkeys. Nature Medicine, 3(1), 73–76.
Curt, A., Van Hedel, H. J., Klaus, D., Dietz, V., & Group, E.-S. S. (2008).
Recovery from a spinal cord injury: Significance of compensation, neu-
ral plasticity, and repair. Journal of Neurotrauma, 25(6), 677–685.
https://doi.org/10.1089/neu.2007.0468
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., …
Gan, W. B. (2005). ATP mediates rapid microglial response to local
brain injury in vivo. Nature Neuroscience, 8(6), 752–758. https://doi.
org/10.1038/nn1472
de Castro, R., Jr., Tajrishi, R., Claros, J., & Stallcup, W. B. (2005). Differen-
tial responses of spinal axons to transection: Influence of the NG2 pro-
teoglycan. Experimental Neurology, 192(2), 299–309. https://doi.org/
10.1016/j.expneurol.2004.11.027
de Faria, O., Jr., Pama, E. A. C., Evans, K., Luzhynskaya, A., &
Karadottir, R. T. (2018). Neuroglial interactions underpinning myelin
plasticity. Developmental Neurobiology, 78(2), 93–107. https://doi.org/
10.1002/dneu.22539
Deshmane, S. L., Kremlev, S., Amini, S., & Sawaya, B. E. (2009). Monocyte
chemoattractant protein-1 (MCP-1): An overview. Journal of Inter-
feron & Cytokine Research, 29(6), 313–326. https://doi.org/10.1089/
jir.2008.0027
Di Maio, A., Skuba, A., Himes, B. T., Bhagat, S. L., Hyun, J. K., Tessler, A., …
Son, Y. J. (2011). In vivo imaging of dorsal root regeneration: Rapid
immobilization and presynaptic differentiation at the CNS/PNS
13
border. The Journal of Neuroscience, 31(12), 4569–4582. https://doi.
org/10.1523/JNEUROSCI.4638-10.2011
Dias, D. O., Kim, H., Holl, D., Werne Solnestam, B., Lundeberg, J.,
Carlen, M., … Frisen, J. (2018). Reducing pericyte-derived scarring pro-
motes recovery after spinal cord injury. Cell, 173(1), 153–165 e122.
https://doi.org/10.1016/j.cell.2018.02.004
Dimou, L., Simon, C., Kirchhoff, F., Takebayashi, H., & Gotz, M. (2008).
Progeny of Olig2-expressing progenitors in the gray and white matter
of the adult mouse cerebral cortex. The Journal of Neuroscience, 28(41),
10434–10442. https://doi.org/10.1523/JNEUROSCI.2831-08.2008
Duncan, G. J., Assinck, P., & Hilton, B. J. (2014). Canonical Wnt signalling
in PDGFRalpha-expressing cells is a critical regulator of astrogliosis
and axon regeneration following CNS injury. The Journal of Neurosci-
ence, 34(49), 16163–16165. https://doi.org/10.1523/JNEUROSCI.
4052-14.2014
Duncan, G. J., Manesh, S. B., Hilton, B. J., Assinck, P., Liu, J., Moulson, A.,
… Tetzlaff, W. (2018). Locomotor recovery following contusive spinal
cord injury does not require oligodendrocyte remyelination. Nature
Communications, 9(1), 3066. https://doi.org/10.1038/s41467-018-
05473-1
Duncan, G. J., Plemel, J. R., Assinck, P., Manesh, S. B., Muir, F. G. W.,
Hirata, R., … Tetzlaff, W. (2017). Myelin regulatory factor drives
remyelination in multiple sclerosis. Acta Neuropathologica, 134,
403–422. https://doi.org/10.1007/s00401-017-1741-7
Duncan, I. D., Radcliff, A. B., Heidari, M., Kidd, G., August, B. K., &
Wierenga, L. A. (2018). The adult oligodendrocyte can participate in
remyelination. Proceedings of the National Academy of Sciences of the
United States of America, 115, E11807–E11816. https://doi.org/10.
1073/pnas.1808064115
Dupouey, P., Jacque, C., Bourre, J. M., Cesselin, F., Privat, A., &
Baumann, N. (1979). Immunochemical studies of myelin basic protein
in shiverer mouse devoid of major dense line of myelin. Neuroscience
Letters, 12(1), 113–118.
Dutta, D. J., Woo, D. H., Lee, P. R., Pajevic, S., Bukalo, O., Huffman, W. C.,
… Fields, R. D. (2018). Regulation of myelin structure and conduction
velocity by perinodal astrocytes. Proceedings of the National Academy
of Sciences of the United States of America, 115(46), 11832–11837.
https://doi.org/10.1073/pnas.1811013115
Dyck, S., Kataria, H., Akbari-Kelachayeh, K., Silver, J., & Karimi-
Abdolrezaee, S. (2019). LAR and PTPsigma receptors are negative reg-
ulators of oligodendrogenesis and oligodendrocyte integrity in spinal
cord injury. Glia, 67(1), 125–145. https://doi.org/10.1002/glia.23533
Dyck, S., Kataria, H., Alizadeh, A., Santhosh, K. T., Lang, B., Silver, J., &
Karimi-Abdolrezaee, S. (2018). Perturbing chondroitin sulfate proteo-
glycan signaling through LAR and PTPsigma receptors promotes a ben-
eficial inflammatory response following spinal cord injury. Journal of
Neuroinflammation, 15(1), 90. https://doi.org/10.1186/s12974-018-
1128-2
Edgar, J. M., McLaughlin, M., Werner, H. B., McCulloch, M. C., Barrie, J. A.,
Brown, A., … Griffiths, I. R. (2009). Early ultrastructural defects of
axons and axon-glia junctions in mice lacking expression of Cnp1. Glia,
57(16), 1815–1824. https://doi.org/10.1002/glia.20893
Ehrlich, M., Mozafari, S., Glatza, M., Starost, L., Velychko, S.,
Hallmann, A. L., … Kuhlmann, T. (2017). Rapid and efficient generation
of oligodendrocytes from human induced pluripotent stem cells using
transcription factors. Proceedings of the National Academy of Sciences
of the United States of America, 114(11), E2243–E2252. https://doi.
org/10.1073/pnas.1614412114
Emery, B., Agalliu, D., Cahoy, J. D., Watkins, T. A., Dugas, J. C.,
Mulinyawe, S. B., … Barres, B. A. (2009). Myelin gene regulatory factor is a
critical transcriptional regulator required for CNS myelination. Cell, 138(1),
172–185. https://doi.org/10.1016/j.cell.2009.04.031
England, J. D., Gamboni, F., & Levinson, S. R. (1991). Increased numbers of
sodium channels form along demyelinated axons. Brain Research, 548
(1–2), 334–337.
14
England, J. D., Gamboni, F., Levinson, S. R., & Finger, T. E. (1990). Changed
distribution of sodium channels along demyelinated axons. Proceedings
of the National Academy of Sciences of the United States of America, 87
(17), 6777–6780.
Etxeberria, A., Hokanson, K. C., Dao, D. Q., Mayoral, S. R., Mei, F.,
Redmond, S. A., … Chan, J. R. (2016). Dynamic modulation of mye-
lination in response to visual stimuli alters optic nerve conduction
velocity. The Journal of Neuroscience, 36(26), 6937–6948. https://doi.
org/10.1523/JNEUROSCI.0908-16.2016
Falcao, A. M., van Bruggen, D., Marques, S., Meijer, M., Jakel, S., Agirre, E.,
… Castelo-Branco, G. (2018). Disease-specific oligodendrocyte lineage
cells arise in multiple sclerosis. Nature Medicine, 24(12), 1837–1844.
https://doi.org/10.1038/s41591-018-0236-y
Faulkner, J. R., Herrmann, J. E., Woo, M. J., Tansey, K. E., Doan, N. B., &
Sofroniew, M. V. (2004). Reactive astrocytes protect tissue and pre-
serve function after spinal cord injury. The Journal of Neuroscience, 24
(9), 2143–2155. https://doi.org/10.1523/JNEUROSCI.3547-03.2004
Felts, P. A., Baker, T. A., & Smith, K. J. (1997). Conduction in segmentally
demyelinated mammalian central axons. The Journal of Neuroscience,
17(19), 7267–7277.
Felts, P. A., & Smith, K. J. (1987). Schwann-cell Remyelination of
demyelinated central nerve-fibers restores secure conduction. Neuro-
pathology and Applied Neurobiology, 13(6), 494–494.
Fernandez-Castaneda, A., & Gaultier, A. (2016). Adult oligodendrocyte
progenitor cells––Multifaceted regulators of the CNS in health and
disease. Brain, Behavior, and Immunity, 57, 1–7. https://doi.org/10.
1016/j.bbi.2016.01.005
Filli, L., Zorner, B., Weinmann, O., & Schwab, M. E. (2011). Motor deficits
and recovery in rats with unilateral spinal cord hemisection mimic the
Brown-Sequard syndrome. Brain, 134(Pt 8), 2261–2273. https://doi.
org/10.1093/brain/awr167
Filous, A. R., Tran, A., Howell, C. J., Busch, S. A., Evans, T. A.,
Stallcup, W. B., … Silver, J. (2014). Entrapment via synaptic-like con-
nections between NG2 proteoglycan+ cells and dystrophic axons in
the lesion plays a role in regeneration failure after spinal cord injury.
The Journal of Neuroscience, 34(49), 16369–16384. https://doi.org/10.
1523/JNEUROSCI.1309-14.2014
Foerster, S., Hill, M. F. E., & Franklin, R. J. M. (2019). Diversity in the oligo-
dendrocyte lineage: Plasticity or heterogeneity? Glia., 67(10), 1797–
1805. https://doi.org/10.1002/glia.23607
Fogarty, M., Richardson, W. D., & Kessaris, N. (2005). A subset of oligo-
dendrocytes generated from radial glia in the dorsal spinal cord. Devel-
opment, 132(8), 1951–1959. https://doi.org/10.1242/dev.01777
Ford, M. C., Alexandrova, O., Cossell, L., Stange-Marten, A., Sinclair, J.,
Kopp-Scheinpflug, C., … Grothe, B. (2015). Tuning of Ranvier node and
internode properties in myelinated axons to adjust action potential
timing. Nature Communications, 6, 8073. https://doi.org/10.1038/
ncomms9073
Gallo, V., Mangin, J. M., Kukley, M., & Dietrich, D. (2008). Synapses on
NG2-expressing progenitors in the brain: Multiple functions? The Jour-
nal of Physiology, 586(16), 3767–3781. https://doi.org/10.1113/
jphysiol.2008.158436
Gallo, V., Zhou, J. M., McBain, C. J., Wright, P., Knutson, P. L., &
Armstrong, R. C. (1996). Oligodendrocyte progenitor cell proliferation
and lineage progression are regulated by glutamate receptor-mediated
K+ channel block. The Journal of Neuroscience, 16(8), 2659–2670.
Gauthier, M. K., Kosciuczyk, K., Tapley, L., & Karimi-Abdolrezaee, S.
(2013). Dysregulation of the neuregulin-1-ErbB network modulates
endogenous oligodendrocyte differentiation and preservation after
spinal cord injury. The European Journal of Neuroscience, 38(5),
2693–2715. https://doi.org/10.1111/ejn.12268
Gautier, H. O., Evans, K. A., Volbracht, K., James, R., Sitnikov, S., Lundgaard, I.,
… Karadottir, R. T. (2015). Neuronal activity regulates remyelination via
glutamate signalling to oligodendrocyte progenitors. Nature Communica-
tions, 6, 8518. https://doi.org/10.1038/ncomms9518
DUNCAN ET AL.
Giacci, M. K., Bartlett, C. A., Smith, N. M., Iyer, K. S., Toomey, L. M., Jiang, H., …
Fitzgerald, M. (2018). Oligodendroglia are particularly vulnerable to oxida-
tive damage after Neurotrauma in vivo. The Journal of Neuroscience, 38
(29), 6491–6504. https://doi.org/10.1523/JNEUROSCI.1898-17.2018
Gibson, E. M., Purger, D., Mount, C. W., Goldstein, A. K., Lin, G. L., Wood, L. S.,
… Monje, M. (2014). Neuronal activity promotes oligodendrogenesis and
adaptive myelination in the mammalian brain. Science, 344(6183),
1252304. https://doi.org/10.1126/science.1252304
Goldman, S. A., & Kuypers, N. J. (2015). How to make an oligodendrocyte.
Development, 142(23), 3983–3995. https://doi.org/10.1242/dev.
126409
Goldschmidt, T., Antel, J., Konig, F. B., Bruck, W., & Kuhlmann, T. (2009).
Remyelination capacity of the MS brain decreases with disease chro-
nicity. Neurology, 72(22), 1914–1921. https://doi.org/10.1212/WNL.
0b013e3181a8260a
Goritz, C., Dias, D. O., Tomilin, N., Barbacid, M., Shupliakov, O., & Frisen, J.
(2011). A pericyte origin of spinal cord scar tissue. Science, 333(6039),
238–242. https://doi.org/10.1126/science.1203165
Griffiths, I., Klugmann, M., Anderson, T., Yool, D., Thomson, C.,
Schwab, M. H., … Nave, K. A. (1998). Axonal swellings and degenera-
tion in mice lacking the major proteolipid of myelin. Science, 280
(5369), 1610–1613.
Guest, J. D., Hiester, E. D., & Bunge, R. P. (2005). Demyelination and
Schwann cell responses adjacent to injury epicenter cavities following
chronic human spinal cord injury. Experimental Neurology, 192(2),
384–393. https://doi.org/10.1016/j.expneurol.2004.11.033
Guizar-Sahagun, G., Grijalva, I., Salgado-Ceballos, H., Espitia, A., Orozco, S.,
Ibarra, A., … Madrazo, I. (2004). Spontaneous and induced aberrant
sprouting at the site of injury is irrelevant to motor function outcome
in rats with spinal cord injury. Brain Research, 1013(2), 143–151.
https://doi.org/10.1016/j.brainres.2004.03.062
Hackett, A. R., Lee, D. H., Dawood, A., Rodriguez, M., Funk, L.,
Tsoulfas, P., & Lee, J. K. (2016). STAT3 and SOCS3 regulate NG2 cell
proliferation and differentiation after contusive spinal cord injury. Neu-
robiology of Disease, 89, 10–22. https://doi.org/10.1016/j.nbd.2016.
01.017
Hackett, A. R., Yahn, S. L., Lyapichev, K., Dajnoki, A., Lee, D. H.,
Rodriguez, M., … Lee, J. K. (2018). Injury type-dependent differentia-
tion of NG2 glia into heterogeneous astrocytes. Experimental Neurol-
ogy, 308, 72–79. https://doi.org/10.1016/j.expneurol.2018.07.001
Hains, B. C., Saab, C. Y., Lo, A. C., & Waxman, S. G. (2004). Sodium channel
blockade with phenytoin protects spinal cord axons, enhances axonal
conduction, and improves functional motor recovery after contusion
SCI. Experimental Neurology, 188(2), 365–377. https://doi.org/10.
1016/j.expneurol.2004.04.001
Hamanaka, G., Ohtomo, R., Takase, H., Lok, J., & Arai, K. (2018). Role of
oligodendrocyte-neurovascular unit in white matter repair. Neurosci-
ence Letters, 684, 175–180. https://doi.org/10.1016/j.neulet.2018.
07.016
Hamilton, N. B., Clarke, L. E., Arancibia-Carcamo, I. L., Kougioumtzidou, E.,
Matthey, M., Karadottir, R., … Attwell, D. (2017). Endogenous GABA
controls oligodendrocyte lineage cell number, myelination, and CNS
internode length. Glia, 65(2), 309–321. https://doi.org/10.1002/glia.
23093
Hanna, A. S., Son, Y. J., & Dempsey, R. (2011). Live imaging of dorsal root
regeneration and the resurgence of a forgotten idea. Neurosurgery, 69(2),
N18–N21. https://doi.org/10.1227/01.neu.0000400019.16401.c3
Harris, J. J., & Attwell, D. (2012). The energetics of CNS white matter. The
Journal of Neuroscience, 32(1), 356–371. https://doi.org/10.1523/
JNEUROSCI.3430-11.2012
Hawryluk, G. W. J., Spano, S., Chew, D., Wang, S., Erwin, M.,
Chamankhah, M., … Fehlings, M. G. (2014). An examination of the
mechanisms by which neural precursors augment recovery following
spinal cord injury: A key Role for Remyelination. Cell Transplantation,
23(3), 365–380. https://doi.org/10.3727/096368912x662408
DUNCAN ET AL.
Hayashi, S., & McMahon, A. P. (2002). Efficient recombination in diverse
tissues by a tamoxifen-inducible form of Cre: A tool for temporally
regulated gene activation/inactivation in the mouse. Developmental
Biology, 244(2), 305–318. https://doi.org/10.1006/dbio.2002.0597
Herrmann, J. E., Imura, T., Song, B. B., Qi, J. W., Ao, Y., Nguyen, T. K., …
Sofroniew, M. V. (2008). STAT3 is a critical regulator of astrogliosis
and scar formation after spinal cord injury. Journal of Neuroscience, 28
(28), 7231–7243. https://doi.org/10.1523/Jneurosci.1709-08.2008
Hesp, Z. C., Goldstein, E. Z., Miranda, C. J., Kaspar, B. K., & McTigue, D. M.
(2015). Chronic oligodendrogenesis and remyelination after spinal cord
injury in mice and rats. The Journal of Neuroscience, 35(3), 1274–1290.
https://doi.org/10.1523/JNEUROSCI.2568-14.2015
Hesp, Z. C., Yoseph, R. Y., Suzuki, R., Jukkola, P., Wilson, C.,
Nishiyama, A., & McTigue, D. M. (2018). Proliferating NG2-cell-
dependent angiogenesis and scar formation Alter axon growth and
functional recovery after spinal cord injury in mice. The Journal of Neu-
roscience, 38(6), 1366–1382. https://doi.org/10.1523/JNEUROSCI.
3953-16.2017
Hill, R. A., Li, A. M., & Grutzendler, J. (2018). Lifelong cortical myelin plas-
ticity and age-related degeneration in the live mammalian brain. Nature
Neuroscience, 21, 683–695. https://doi.org/10.1038/s41593-018-
0120-6
Hill, R. A., Patel, K. D., Goncalves, C. M., Grutzendler, J., & Nishiyama, A.
(2014). Modulation of oligodendrocyte generation during a critical
temporal window after NG2 cell division. Nature Neuroscience, 17(11),
1518–1527. https://doi.org/10.1038/nn.3815
Hilton, B. J., Anenberg, E., Harrison, T. C., Boyd, J. D., Murphy, T. H., &
Tetzlaff, W. (2016). Re-establishment of cortical motor output maps
and spontaneous functional recovery via spared Dorsolaterally
projecting Corticospinal neurons after dorsal column spinal cord injury
in adult mice. The Journal of Neuroscience, 36(14), 4080–4092. https://
doi.org/10.1523/JNEUROSCI.3386-15.2016
Hilton, B. J., Moulson, A. J., & Tetzlaff, W. (2017). Neuroprotection and
secondary damage following spinal cord injury: Concepts and
methods. Neuroscience Letters, 652, 3–10. https://doi.org/10.1016/j.
neulet.2016.12.004
Hilton, B. J., & Tetzlaff, W. (2018). A brainstem bypass for spinal cord
injury. Nature Neuroscience, 21(4), 457–458. https://doi.org/10.1038/
s41593-018-0099-z
Hofstetter, C. P., Holmstrom, N. A. V., Lilja, J. A., Schweinhardt, P.,
Hao, J. X., Spenger, C., … Olson, L. (2005). Allodynia limits the useful-
ness of intraspinal neural stem cell grafts; directed differentiation
improves outcome. Nature Neuroscience, 8(3), 346–353. https://doi.
org/10.1038/Nn1405
Honmou, O., Felts, P. A., Waxman, S. G., & Kocsis, J. D. (1996). Restoration
of normal conduction properties in demyelinated spinal cord axons in
the adult rat by transplantation of exogenous Schwann cells. Journal of
Neuroscience, 16(10), 3199–3208.
Horky, L. L., Galimi, F., Gage, F. H., & Horner, P. J. (2006). Fate of endoge-
nous stem/progenitor cells following spinal cord injury. The Journal of
Comparative Neurology, 498(4), 525–538. https://doi.org/10.1002/
cne.21065
Huang, W., Bai, X., Stopper, L., Catalin, B., Cartarozzi, L. P., Scheller, A., &
Kirchhoff, F. (2018). During development NG2 glial cells of the spinal
cord are restricted to the Oligodendrocyte lineage, but generate astro-
cytes upon acute injury. Neuroscience, 385, 154–165. https://doi.org/
10.1016/j.neuroscience.2018.06.015
Huang, W., Guo, Q., Bai, X., Scheller, A., & Kirchhoff, F. (2019). Early
embryonic NG2 glia are exclusively gliogenic and do not generate neu-
rons in the brain. Glia, 67(6), 1094–1103. https://doi.org/10.1002/
glia.23590
Hubscher, C. H., & Johnson, R. D. (2006). Chronic spinal cord injury
induced changes in the responses of thalamic neurons. Experimental
Neurology, 197(1), 177–188. https://doi.org/10.1016/j.expneurol.
2005.09.007
15
Hughes, E. G., Kang, S. H., Fukaya, M., & Bergles, D. E. (2013). Oligoden-
drocyte progenitors balance growth with self-repulsion to achieve
homeostasis in the adult brain. Nature Neuroscience, 16(6), 668–676.
https://doi.org/10.1038/nn.3390
Hughes, E. G., Orthmann-Murphy, J. L., Langseth, A. J., & Bergles, D. E. (2018).
Myelin remodeling through experience-dependent oligodendrogenesis in
the adult somatosensory cortex. Nature Neuroscience, 21(5), 696–706.
https://doi.org/10.1038/s41593-018-0121-5
Hunanyan, A. S., Garcia-Alias, G., Alessi, V., Levine, J. M., Fawcett, J. W.,
Mendell, L. M., & Arvanian, V. L. (2010). Role of chondroitin sulfate
proteoglycans in axonal conduction in mammalian spinal cord. The
Journal of Neuroscience, 30(23), 7761–7769. https://doi.org/10.1523/
JNEUROSCI.4659-09.2010
Hwang, D. H., Kim, B. G., Kim, E. J., Lee, S. I., Joo, I. S., Suh-Kim, H., …
Kim, S. U. (2009). Transplantation of human neural stem cells trans-
duced with Olig2 transcription factor improves locomotor recovery
and enhances myelination in the white matter of rat spinal cord fol-
lowing contusive injury. BMC Neuroscience, 10. doi:Artn 117, 117.
https://doi.org/10.1186/1471-2202-10-117
James, N. D., Bartus, K., Grist, J., Bennett, D. L., McMahon, S. B., &
Bradbury, E. J. (2011). Conduction failure following spinal cord injury:
Functional and anatomical changes from acute to chronic stages. The
Journal of Neuroscience, 31(50), 18543–18555. https://doi.org/10.
1523/JNEUROSCI.4306-11.2011
Jeffery, N. D., & Blakemore, W. F. (1995). Remyelination of mouse spinal
cord axons demyelinated by local injection of lysolecithin. Journal of
Neurocytology, 24(10), 775–781.
Jeffery, N. D., Smith, P. M., Lakatos, A., Ibanez, C., Ito, D., & Franklin, R. J.
(2006). Clinical canine spinal cord injury provides an opportunity to
examine the issues in translating laboratory techniques into practical
therapy. Spinal Cord, 44(10), 584–593. https://doi.org/10.1038/sj.sc.
3101912
Kadoya, K., Tsukada, S., Lu, P., Coppola, G., Geschwind, D., Filbin, M. T., …
Tuszynski, M. H. (2009). Combined intrinsic and extrinsic neuronal
mechanisms facilitate bridging axonal regeneration one year after spi-
nal cord injury. Neuron, 64(2), 165–172. https://doi.org/10.1016/j.
neuron.2009.09.016
Kakulas, A. (1988). The applied neurobiology of human spinal cord injury:
A review. Paraplegia, 26(6), 371–379. https://doi.org/10.1038/sc.
1988.57
Kakulas, B. A. (2004). Neuropathology: The foundation for new treatments
in spinal cord injury. Spinal Cord, 42(10), 549–563. https://doi.org/10.
1038/sj.sc.3101670
Kakulas, B. A., & Kaelan, C. (2015). The neuropathological foundations for
the restorative neurology of spinal cord injury. Clinical Neurology and
Neurosurgery, 129(Suppl 1), S1–S7. https://doi.org/10.1016/j.clineuro.
2015.01.012
Kang, S. H., Fukaya, M., Yang, J. K., Rothstein, J. D., & Bergles, D. E.
(2010). NG2+ CNS glial progenitors remain committed to the oligo-
dendrocyte lineage in postnatal life and following neurodegeneration.
Neuron, 68(4), 668–681. https://doi.org/10.1016/j.neuron.2010.
09.009
Kang, Z., Wang, C., Zepp, J., Wu, L., Sun, K., Zhao, J., … Li, X. (2013). Act1
mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial
cells. Nature Neuroscience, 16(10), 1401–1408. https://doi.org/10.
1038/nn.3505
Kanno, H., Pearse, D. D., Ozawa, H., Itoi, E., & Bunge, M. B. (2015).
Schwann cell transplantation for spinal cord injury repair: Its significant
therapeutic potential and prospectus. Reviews in the Neurosciences, 26
(2), 121–128. https://doi.org/10.1515/revneuro-2014-0068
Karadottir, R., Hamilton, N. B., Bakiri, Y., & Attwell, D. (2008). Spiking and non-
spiking classes of oligodendrocyte precursor glia in CNS white matter.
Nature Neuroscience, 11(4), 450–456. https://doi.org/10.1038/nn2060
Karimi-Abdolrezaee, S., Eftekharpour, E., & Fehlings, M. G. (2004). Tempo-
ral and spatial patterns of Kv1.1 and Kv1.2 protein and gene
16
expression in spinal cord white matter after acute and chronic spinal
cord injury in rats: Implications for axonal pathophysiology after
neurotrauma. The European Journal of Neuroscience, 19(3), 577–589.
Karimi-Abdolrezaee, S., Eftekharpour, E., Wang, J., Morshead, C. M., &
Fehlings, M. G. (2006). Delayed transplantation of adult neural precur-
sor cells promotes remyelination and functional neurological recovery
after spinal cord injury. Journal of Neuroscience, 26(13), 3377–3389.
https://doi.org/10.1523/Jneurosci.4184-05.2006
Karimi-Abdolrezaee, S., Eftekharpour, E., Wang, J., Schut, D., &
Fehlings, M. G. (2010). Synergistic effects of transplanted adult neural
stem/progenitor cells, chondroitinase, and growth factors promote
functional repair and plasticity of the chronically injured spinal cord.
The Journal of Neuroscience, 30(5), 1657–1676. https://doi.org/10.
1523/JNEUROSCI.3111-09.2010
Kataria, H., Alizadeh, A., Shahriary, G. M., Saboktakin Rizi, S., Henrie, R.,
Santhosh, K. T., … Karimi-Abdolrezaee, S. (2018). Neuregulin-1 pro-
motes remyelination and fosters a pro-regenerative inflammatory
response in focal demyelinating lesions of the spinal cord. Glia, 66(3),
538–561. https://doi.org/10.1002/glia.23264
Keirstead, H. S., Nistor, G., Bernal, G., Totoiu, M., Cloutier, F., Sharp, K., &
Steward, O. (2005). Human embryonic stem cell-derived oligodendro-
cyte progenitor cell transplants remyelinate and restore locomotion
after spinal cord injury. The Journal of Neuroscience, 25(19),
4694–4705. https://doi.org/10.1523/JNEUROSCI.0311-05.2005
Keough, M. B., Rogers, J. A., Zhang, P., Jensen, S. K., Stephenson, E. L.,
Chen, T., … Yong, V. W. (2016). An inhibitor of chondroitin sulfate pro-
teoglycan synthesis promotes central nervous system remyelination.
Nature Communications, 7, 11312. https://doi.org/10.1038/
ncomms11312
Kirby, L., Jin, J., Gonzalez-Cardona, J., Smith, M., Martin, K., Wang, J., …
Calabresi, P. A. (2018). Oligodendrocyte precursor cells are co-opted
by the immune system to cross-present antigen and mediate cytotox-
icity. bioRxiv, 461434. https://doi.org/10.1101/461434
Kirschner, D. A., & Ganser, A. L. (1980). Compact myelin exists in the
absence of basic protein in the shiverer mutant mouse. Nature, 283
(5743), 207–210.
Kukley, M., Capetillo-Zarate, E., & Dietrich, D. (2007). Vesicular glutamate
release from axons in white matter. Nature Neuroscience, 10(3),
311–320. https://doi.org/10.1038/nn1850
Kwon, B. K., Tetzlaff, W., Grauer, J. N., Beiner, J., & Vaccaro, A. R. (2004).
Pathophysiology and pharmacologic treatment of acute spinal cord
injury. The Spine Journal, 4(4), 451–464. https://doi.org/10.1016/j.
spinee.2003.07.007
Lachapelle, F., Bachelin, C., Moissonnier, P., Nait-Oumesmar, B.,
Hidalgo, A., Fontaine, D., & Baron-Van Evercooren, A. (2005). Failure
of remyelination in the nonhuman primate optic nerve. Brain Pathol-
ogy, 15(3), 198–207.
Lasiene, J., Shupe, L., Perlmutter, S., & Horner, P. (2008). No evidence for
chronic demyelination in spared axons after spinal cord injury in a
mouse. The Journal of Neuroscience, 28(15), 3887–3896. https://doi.
org/10.1523/JNEUROSCI.4756-07.2008
Lee, Y., Morrison, B. M., Li, Y., Lengacher, S., Farah, M. H., Hoffman, P. N.,
… Rothstein, J. D. (2012). Oligodendroglia metabolically support axons
and contribute to neurodegeneration. Nature, 487(7408), 443–448.
https://doi.org/10.1038/nature11314
Lehninger, A. L., Vercesi, A., & Bababunmi, E. A. (1978). Regulation of Ca2
+ release from mitochondria by the oxidation-reduction state of pyri-
dine nucleotides. Proceedings of the National Academy of Sciences of
the United States of America, 75(4), 1690–1694.
Li, Y., & Raisman, G. (1995). Sprouts from cut corticospinal axons persist in
the presence of astrocytic scarring in long-term lesions of the adult rat
spinal cord. Experimental Neurology, 134(1), 102–111. https://doi.org/
10.1006/exnr.1995.1041
DUNCAN ET AL.
Lillie, R. S. (1925). Factors affecting transmission and recovery in the pas-
sive iron nerve model. Journal of General Physiology, 7(4), 473–507.
https://doi.org/10.1085/Jgp.7.4.473
Liu, J., Dietz, K., DeLoyht, J. M., Pedre, X., Kelkar, D., Kaur, J., …
Casaccia, P. (2012). Impaired adult myelination in the prefrontal cortex
of socially isolated mice. Nature Neuroscience, 15(12), 1621–1623.
https://doi.org/10.1038/nn.3263
Liu, S., Yin, F., Zhang, J., & Qian, Y. (2014). The role of calpains in traumatic
brain injury. Brain Injury, 28(2), 133–137. https://doi.org/10.3109/
02699052.2013.860479
Liuzzi, F. J., & Lasek, R. J. (1987). Astrocytes block axonal regeneration in
mammals by activating the physiological stop pathway. Science, 237
(4815), 642–645.
Ma, D., Wang, B., Zawadzka, M., Gonzalez, G., Wu, Z., Yu, B., … Zhao, C.
(2018). A subpopulation of Foxj1-expressing, Nonmyelinating
Schwann cells of the peripheral nervous system contribute to
Schwann cell Remyelination in the central nervous system. The Journal
of Neuroscience, 38(43), 9228–9239. https://doi.org/10.1523/
JNEUROSCI.0585-18.2018
Makinodan, M., Rosen, K. M., Ito, S., & Corfas, G. (2012). A critical period
for social experience-dependent oligodendrocyte maturation and mye-
lination. Science, 337(6100), 1357–1360. https://doi.org/10.1126/
science.1220845
Marques, S., van Bruggen, D., Vanichkina, D. P., Floriddia, E. M.,
Munguba, H., Varemo, L., … Castelo-Branco, G. (2018). Transcriptional
convergence of Oligodendrocyte lineage progenitors during develop-
ment. Developmental Cell, 46(4), 504–517 e507. https://doi.org/10.
1016/j.devcel.2018.07.005
McTigue, D. M., Horner, P. J., Stokes, B. T., & Gage, F. H. (1998). Neuro-
trophin-3 and brain-derived neurotrophic factor induce oligodendro-
cyte proliferation and myelination of regenerating axons in the
contused adult rat spinal cord. The Journal of Neuroscience, 18(14),
5354–5365.
McTigue, D. M., Tripathi, R., & Wei, P. (2006). NG2 colocalizes with axons
and is expressed by a mixed cell population in spinal cord lesions. Jour-
nal of Neuropathology and Experimental Neurology, 65(4), 406–420.
https://doi.org/10.1097/01.jnen.0000218447.32320.52
McTigue, D. M., Wei, P., & Stokes, B. T. (2001). Proliferation of
NG2-positive cells and altered oligodendrocyte numbers in the con-
tused rat spinal cord. The Journal of Neuroscience, 21(10), 3392–3400.
Mei, F., Lehmann-Horn, K., Shen, Y. A., Rankin, K. A., Stebbins, K. J.,
Lorrain, D. S., … Chan, J. R. (2016). Accelerated remyelination during
inflammatory demyelination prevents axonal loss and improves func-
tional recovery. eLife, 5, 5. https://doi.org/10.7554/eLife.18246
Metz, G. A., Curt, A., van de Meent, H., Klusman, I., Schwab, M. E., &
Dietz, V. (2000). Validation of the weight-drop contusion model in
rats: A comparative study of human spinal cord injury. Journal of
Neurotrauma, 17(1), 1–17. https://doi.org/10.1089/neu.2000.17.1
Michailov, G. V., Sereda, M. W., Brinkmann, B. G., Fischer, T. M., Haug, B.,
Birchmeier, C., … Nave, K. A. (2004). Axonal neuregulin-1 regulates
myelin sheath thickness. Science, 304(5671), 700–703. https://doi.
org/10.1126/science.1095862
Mitew, S., Gobius, I., Fenlon, L. R., McDougall, S. J., Hawkes, D., Xing, Y. L.,
… Emery, B. (2018). Pharmacogenetic stimulation of neuronal activity
increases myelination in an axon-specific manner. Nature Communica-
tions, 9(1), 306. https://doi.org/10.1038/s41467-017-02719-2
Monteiro de Castro, G., Deja, N. A., Ma, D., Zhao, C., & Franklin, R. J.
(2015). Astrocyte activation via Stat3 signaling determines the balance
of Oligodendrocyte versus Schwann cell Remyelination. The American
Journal of Pathology, 185(9), 2431–2440. https://doi.org/10.1016/j.
ajpath.2015.05.011
Moyon, S., Dubessy, A. L., Aigrot, M. S., Trotter, M., Huang, J. K.,
Dauphinot, L., … Lubetzki, C. (2015). Demyelination causes adult CNS
progenitors to revert to an immature state and express immune cues
DUNCAN ET AL.
that support their migration. The Journal of Neuroscience, 35(1), 4–20.
https://doi.org/10.1523/JNEUROSCI.0849-14.2015
Murray, K. C., Nakae, A., Stephens, M. J., Rank, M., D'Amico, J.,
Harvey, P. J., … Fouad, K. (2010). Recovery of motoneuron and loco-
motor function after spinal cord injury depends on constitutive activity
in 5-HT2C receptors. Nature Medicine, 16(6), 694–700. https://doi.
org/10.1038/nm.2160
Myers, S. A., Bankston, A. N., Burke, D. A., Ohri, S. S., & Whittemore, S. R.
(2016). Does the preclinical evidence for functional remyelination fol-
lowing myelinating cell engraftment into the injured spinal cord sup-
port progression to clinical trials? Experimental Neurology, 283(Pt B),
560–572. https://doi.org/10.1016/j.expneurol.2016.04.009
Nashmi, R., & Fehlings, M. G. (2001). Mechanisms of axonal dysfunction
after spinal cord injury: With an emphasis on the role of voltage-gated
potassium channels. Brain Research. Brain Research Reviews, 38(1–2),
165–191.
Nave, K. A. (2010). Myelination and support of axonal integrity by glia.
Nature, 468(7321), 244–252. https://doi.org/10.1038/nature09614
Nave, K. A., & Werner, H. B. (2014). Myelination of the nervous system:
Mechanisms and functions. Annual Review of Cell and Developmental
Biology, 30, 503–533. https://doi.org/10.1146/annurev-cellbio-
100913-013101
Nishiyama, A., Lin, X. H., Giese, N., Heldin, C. H., & Stallcup, W. B. (1996).
Co-localization of NG2 proteoglycan and PDGF alpha-receptor on
O2A progenitor cells in the developing rat brain. Journal of Neurosci-
ence Research, 43(3), 299–314.
Norenberg, M. D., Smith, J., & Marcillo, A. (2004). The pathology of human
spinal cord injury: Defining the problems. Journal of Neurotrauma, 21
(4), 429–440. https://doi.org/10.1089/089771504323004575
Nori, S., Khazaei, M., Ahuja, C. S., Yokota, K., Ahlfors, J. E., Liu, Y., …
Fehlings, M. G. (2018). Human Oligodendrogenic neural progenitor
cells delivered with Chondroitinase ABC facilitate functional repair of
chronic spinal cord injury. Stem Cell Reports, 11(6), 1433–1448.
https://doi.org/10.1016/j.stemcr.2018.10.017
Oblinger, M. M., Foe, L. G., Kwiatkowska, D., & Kemp, R. G. (1988). Phos-
phofructokinase in the rat nervous system: Regional differences in
activity and characteristics of axonal transport. Journal of Neuroscience
Research, 21(1), 25–34. https://doi.org/10.1002/jnr.490210105
Okubo, T., Nagoshi, N., Kohyama, J., Tsuji, O., Shinozaki, M., Shibata, S., …
Okano, H. (2018). Treatment with a gamma-Secretase inhibitor pro-
motes functional recovery in human iPSC- derived transplants for
chronic spinal cord injury. Stem Cell Reports, 11(6), 1416–1432.
https://doi.org/10.1016/j.stemcr.2018.10.022
Pallini, R., Fernandez, E., & Sbriccoli, A. (1988). Retrograde degeneration of
corticospinal axons following transection of the spinal cord in rats. A
quantitative study with anterogradely transported horseradish peroxi-
dase. Journal of Neurosurgery, 68(1), 124–128. https://doi.org/10.
3171/jns.1988.68.1.0124
Papastefanaki, F., & Matsas, R. (2015). From demyelination to
remyelination: The road toward therapies for spinal cord injury. Glia,
63(7), 1101–1125. https://doi.org/10.1002/glia.22809
Patrikios, P., Stadelmann, C., Kutzelnigg, A., Rauschka, H.,
Schmidbauer, M., Laursen, H., … Lassmann, H. (2006). Remyelination is
extensive in a subset of multiple sclerosis patients. Brain, 129,
3165–3172. https://doi.org/10.1093/Brain/Awl217
Pearse, D. D., Pereira, F. C., Marcillo, A. E., Bates, M. L., Berrocal, Y. A.,
Filbin, M. T., & Bunge, M. B. (2004). cAMP and Schwann cells promote
axonal growth and functional recovery after spinal cord injury. Nature
Medicine, 10(6), 610–616. https://doi.org/10.1038/Nm1056
Pedraza, L., Huang, J. K., & Colman, D. (2009). Disposition of axonal caspr
with respect to glial cell membranes: Implications for the process of
myelination. Journal of Neuroscience Research, 87(15), 3480–3491.
https://doi.org/10.1002/jnr.22004
Peles, E., Nativ, M., Lustig, M., Grumet, M., Schilling, J., Martinez, R., …
Schlessinger, J. (1997). Identification of a novel contactin-associated
17
transmembrane receptor with multiple domains implicated in protein-
protein interactions. The EMBO Journal, 16(5), 978–988. https://doi.
org/10.1093/emboj/16.5.978
Petrosyan, H. A., Hunanyan, A. S., Alessi, V., Schnell, L., Levine, J., &
Arvanian, V. L. (2013). Neutralization of inhibitory molecule NG2
improves synaptic transmission, retrograde transport, and locomotor
function after spinal cord injury in adult rats. The Journal of Neuroscience,
33(9), 4032–4043. https://doi.org/10.1523/JNEUROSCI.4702-12.2013
Pham, L. D., Hayakawa, K., Seo, J. H., Nguyen, M. N., Som, A. T., Lee, B. J.,
… Arai, K. (2012). Crosstalk between oligodendrocytes and cerebral
endothelium contributes to vascular remodeling after white matter
injury. Glia, 60(6), 875–881. https://doi.org/10.1002/glia.22320
Philips, T., & Rothstein, J. D. (2017). Oligodendroglia: Metabolic supporters
of neurons. The Journal of Clinical Investigation, 127(9), 3271–3280.
https://doi.org/10.1172/JCI90610
Piltti, K. M., Funes, G. M., Avakian, S. N., Salibian, A. A., Huang, K. I.,
Carta, K., … Anderson, A. J. (2017). Increasing human neural stem cell
transplantation dose alters Oligodendroglial and neuronal differentia-
tion after spinal cord injury. Stem Cell Reports, 8(6), 1534–1548.
https://doi.org/10.1016/j.stemcr.2017.04.009
Plemel, J. R., Keough, M. B., Duncan, G. J., Sparling, J. S., Yong, V. W.,
Stys, P. K., & Tetzlaff, W. (2014). Remyelination after spinal cord
injury: Is it a target for repair? Progress in Neurobiology, 117, 54–72.
https://doi.org/10.1016/j.pneurobio.2014.02.006
Plemel, J. R., Manesh, S. B., Sparling, J. S., & Tetzlaff, W. (2013). Myelin
inhibits oligodendroglial maturation and regulates oligodendrocytic
transcription factor expression. Glia, 61(9), 1471–1487. https://doi.
org/10.1002/Glia.22535
Posmantur, R., Kampfl, A., Siman, R., Liu, J., Zhao, X., Clifton, G. L., &
Hayes, R. L. (1997). A calpain inhibitor attenuates cortical cytoskeletal
protein loss after experimental traumatic brain injury in the rat. Neuro-
science, 77(3), 875–888.
Powers, B. E., Lasiene, J., Plemel, J. R., Shupe, L., Perlmutter, S. I.,
Tetzlaff, W., & Horner, P. J. (2012). Axonal thinning and extensive
remyelination without chronic demyelination in spinal injured rats. The
Journal of Neuroscience, 32(15), 5120–5125. https://doi.org/10.1523/
JNEUROSCI.0002-12.2012
Powers, B. E., Sellers, D. L., Lovelett, E. A., Cheung, W., Aalami, S. P.,
Zapertov, N., … Horner, P. J. (2013). Remyelination reporter reveals
prolonged refinement of spontaneously regenerated myelin. Proceed-
ings of the National Academy of Sciences of the United States of America,
110(10), 4075–4080. https://doi.org/10.1073/pnas.1210293110
Pringle, N. P., Mudhar, H. S., Collarini, E. J., & Richardson, W. D. (1992).
PDGF receptors in the rat CNS: During late neurogenesis, PDGF
alpha-receptor expression appears to be restricted to glial cells of the
oligodendrocyte lineage. Development, 115(2), 535–551.
Pringle, N. P., & Richardson, W. D. (1993). A singularity of PDGF alpha-
receptor expression in the dorsoventral axis of the neural tube may define
the origin of the oligodendrocyte lineage. Development, 117(2), 525–533.
Pu, A., Stephenson, E. L., & Yong, V. W. (2018). The extracellular matrix: Focus
on oligodendrocyte biology and targeting CSPGs for remyelination thera-
pies. Glia, 66(9), 1809–1825. https://doi.org/10.1002/glia.23333
Pukos, N., Goodus, M. T., Sahinkaya, F. R., & McTigue, D. (2019). Persis-
tent oligodendrocyte formation and remyelination occurs in a dynamic
microenvironment after spinal cord injury. Glia, in press.
Raff, M. C., Lillien, L. E., Richardson, W. D., Burne, J. F., & Noble, M. D.
(1988). Platelet-derived growth factor from astrocytes drives the clock
that times oligodendrocyte development in culture. Nature, 333(6173),
562–565. https://doi.org/10.1038/333562a0
Raineteau, O., Fouad, K., Bareyre, F. M., & Schwab, M. E. (2002). Reorgani-
zation of descending motor tracts in the rat spinal cord. The European
Journal of Neuroscience, 16(9), 1761–1771.
Ramer, M. S., Priestley, J. V., & McMahon, S. B. (2000). Functional regener-
ation of sensory axons into the adult spinal cord. Nature, 403(6767),
312–316. https://doi.org/10.1038/35002084
18
Rasband, M. N., Trimmer, J. S., Schwarz, T. L., Levinson, S. R.,
Ellisman, M. H., Schachner, M., & Shrager, P. (1998). Potassium chan-
nel distribution, clustering, and function in remyelinating rat axons.
The Journal of Neuroscience, 18(1), 36–47.
Redford, E. J., Kapoor, R., & Smith, K. J. (1997). Nitric oxide donors revers-
ibly block axonal conduction: Demyelinated axons are especially sus-
ceptible. Brain, 120(Pt 12), 2149–2157.
Rempe, R. G., Hartz, A. M. S., & Bauer, B. (2016). Matrix
metalloproteinases in the brain and blood-brain barrier: Versatile brea-
kers and makers. Journal of Cerebral Blood Flow and Metabolism, 36(9),
1481–1507. https://doi.org/10.1177/0271678X16655551
Richardson, W. D., Pringle, N., Mosley, M. J., Westermark, B., & Dubois-
Dalcq, M. (1988). A role for platelet-derived growth factor in normal
gliogenesis in the central nervous system. Cell, 53(2), 309–319.
Rodriguez, J. P., Coulter, M., Miotke, J., Meyer, R. L., Takemaru, K., &
Levine, J. M. (2014). Abrogation of beta-catenin signaling in oligoden-
drocyte precursor cells reduces glial scarring and promotes axon
regeneration after CNS injury. The Journal of Neuroscience, 34(31),
10285–10297. https://doi.org/10.1523/JNEUROSCI.4915-13.2014
Rossignol, S., & Frigon, A. (2011). Recovery of locomotion after spinal cord
injury: Some facts and mechanisms. Annual Review of Neuroscience, 34,
413–440. https://doi.org/10.1146/annurev-neuro-061010-113746
Saab, A. S., & Nave, K. A. (2017). Myelin dynamics: Protecting and shaping
neuronal functions. Current Opinion in Neurobiology, 47, 104–112.
https://doi.org/10.1016/j.conb.2017.09.013
Sabelstrom, H., Stenudd, M., Reu, P., Dias, D. O., Elfineh, M., Zdunek, S., …
Frisen, J. (2013). Resident neural stem cells restrict tissue damage and
neuronal loss after spinal cord injury in mice. Science, 342(6158),
637–640. https://doi.org/10.1126/science.1242576
Schucht, P., Raineteau, O., Schwab, M. E., & Fouad, K. (2002). Anatomical
correlates of locomotor recovery following dorsal and ventral lesions
of the rat spinal cord. Experimental Neurology, 176(1), 143–153.
Seif, G. I., Nomura, H., & Tator, C. H. (2007). Retrograde axonal degenera-
tion "dieback" in the corticospinal tract after transection injury of the
rat spinal cord: A confocal microscopy study. Journal of Neurotrauma,
24(9), 1513–1528. https://doi.org/10.1089/neu.2007.0323
Sellers, D. L., Maris, D. O., & Horner, P. J. (2009). Postinjury niches induce
temporal shifts in progenitor fates to direct lesion repair after spinal
cord injury. The Journal of Neuroscience, 29(20), 6722–6733. https://
doi.org/10.1523/JNEUROSCI.4538-08.2009
Seo, J. H., Miyamoto, N., Hayakawa, K., Pham, L. D., Maki, T., Ayata, C., …
Arai, K. (2013). Oligodendrocyte precursors induce early blood-brain
barrier opening after white matter injury. The Journal of Clinical Investi-
gation, 123(2), 782–786. https://doi.org/10.1172/JCI65863
Shrager, P., Custer, A. W., Kazarinova, K., Rasband, M. N., & Mattson, D.
(1998). Nerve conduction block by nitric oxide that is mediated by the
axonal environment. Journal of Neurophysiology, 79(2), 529–536.
https://doi.org/10.1152/jn.1998.79.2.529
Shultz, R. B., Wang, Z., Nong, J., Zhang, Z., & Zhong, Y. (2017). Local deliv-
ery of thyroid hormone enhances oligodendrogenesis and myelination
after spinal cord injury. Journal of Neural Engineering, 14(3), 036014.
https://doi.org/10.1088/1741-2552/aa6450
Siebert, J. R., Conta Steencken, A., & Osterhout, D. J. (2014). Chondroitin
sulfate proteoglycans in the nervous system: Inhibitors to repair.
BioMed Research International, 2014, 845315–845323. https://doi.
org/10.1155/2014/845323
Silver, J., Schwab, M. E., & Popovich, P. G. (2014). Central nervous system
regenerative failure: Role of oligodendrocytes, astrocytes, and
microglia. Cold Spring Harbor Perspectives in Biology, 7(3), a020602.
https://doi.org/10.1101/cshperspect.a020602
Smith, K. J., Blakemore, W. F., & Mcdonald, W. I. (1979). Central
remyelination restores secure conduction. Nature, 280(5721),
395–396. https://doi.org/10.1038/280395a0
Smith, P. M., & Jeffery, N. D. (2005). Spinal shock––Comparative aspects and
clinical relevance. Journal of Veterinary Internal Medicine, 19(6), 788–793.
DUNCAN ET AL.
Snaidero, N., Mobius, W., Czopka, T., Hekking, L. H., Mathisen, C.,
Verkleij, D., … Simons, M. (2014). Myelin membrane wrapping of CNS
axons by PI(3,4,5)P3-dependent polarized growth at the inner tongue.
Cell, 156(1–2), 277–290. https://doi.org/10.1016/j.cell.2013.11.044
Snaidero, N., Velte, C., Myllykoski, M., Raasakka, A., Ignatev, A.,
Werner, H. B., … Simons, M. (2017). Antagonistic functions of MBP
and CNP establish cytosolic channels in CNS myelin. Cell Reports, 18
(2), 314–323. https://doi.org/10.1016/j.celrep.2016.12.053
Sofroniew, M. V. (2015). Astrocyte barriers to neurotoxic inflammation.
Nature Reviews. Neuroscience, 16(5), 249–263. https://doi.org/10.
1038/nrn3898
Son, Y. J. (2015). Synapsing with NG2 cells (polydendrocytes),
unappreciated barrier to axon regeneration? Neural Regeneration
Research, 10(3), 346–348. https://doi.org/10.4103/1673-5374.
153672
Spitzer, S. O., Sitnikov, S., Kamen, Y., Evans, K. A., Kronenberg-
Versteeg, D., Dietmann, S., … Karadottir, R. T. (2019). Oligodendrocyte
progenitor cells become regionally diverse and heterogeneous with
age. Neuron, 101, 459–471.e5. https://doi.org/10.1016/j.neuron.
2018.12.020
Stirling, D. P., Khodarahmi, K., Liu, J., McPhail, L. T., McBride, C. B.,
Steeves, J. D., … Tetzlaff, W. (2004). Minocycline treatment reduces
delayed oligodendrocyte death, attenuates axonal dieback, and
improves functional outcome after spinal cord injury. The Journal of
Neuroscience, 24(9), 2182–2190. https://doi.org/10.1523/
JNEUROSCI.5275-03.2004
Stys, P. K., Waxman, S. G., & Ransom, B. R. (1991). Na(+)-Ca2+ exchanger
mediates Ca2+ influx during anoxia in mammalian central nervous sys-
tem white matter. Annals of Neurology, 30(3), 375–380. https://doi.
org/10.1002/ana.410300309
Tan, A. M., Colletti, M., Rorai, A. T., Skene, J. H., & Levine, J. M. (2006).
Antibodies against the NG2 proteoglycan promote the regeneration of
sensory axons within the dorsal columns of the spinal cord. The Journal
of Neuroscience, 26(18), 4729–4739. https://doi.org/10.1523/
JNEUROSCI.3900-05.2006
Tang, D. G., Tokumoto, Y. M., & Raff, M. C. (2000). Long-term culture of
purified postnatal oligodendrocyte precursor cells. Evidence for an
intrinsic maturation program that plays out over months. The Journal
of Cell Biology, 148(5), 971–984. https://doi.org/10.1083/jcb.148.
5.971
Tetzlaff, W., Okon, E. B., Karimi-Abdolrezaee, S., Hill, C. E., Sparling, J. S.,
Plemel, J. R., … Kwon, B. K. (2011). A systematic review of cellular
transplantation therapies for spinal cord injury. Journal of Neurotrauma,
28(8), 1611–1682. https://doi.org/10.1089/neu.2009.1177
Timsit, S., Martinez, S., Allinquant, B., Peyron, F., Puelles, L., & Zalc, B.
(1995). Oligodendrocytes originate in a restricted zone of the embry-
onic ventral neural tube defined by DM-20 mRNA expression. The
Journal of Neuroscience, 15(2), 1012–1024.
Torres-Espin, A., Beaudry, E., Fenrich, K., & Fouad, K. (2018). Rehabilitative
training in animal models of spinal cord injury. Journal of Neurotrauma,
35(16), 1970–1985. https://doi.org/10.1089/neu.2018.5906
Totoiu, M. O., & Keirstead, H. S. (2005). Spinal cord injury is accompanied
by chronic progressive demyelination. The Journal of Comparative Neu-
rology, 486(4), 373–383. https://doi.org/10.1002/cne.20517
Trapp, B. D., & Stys, P. K. (2009). Virtual hypoxia and chronic necrosis of
demyelinated axons in multiple sclerosis. Lancet Neurology, 8(3),
280–291. https://doi.org/10.1016/S1474-4422(09)70043-2
Tripathi, R., & McTigue, D. M. (2007). Prominent oligodendrocyte genesis
along the border of spinal contusion lesions. Glia, 55(7), 698–711.
https://doi.org/10.1002/Glia.20491
Tripathi, R. B., Clarke, L. E., Burzomato, V., Kessaris, N., Anderson, P. N.,
Attwell, D., & Richardson, W. D. (2011). Dorsally and ventrally derived
oligodendrocytes have similar electrical properties but myelinate pre-
ferred tracts. The Journal of Neuroscience, 31(18), 6809–6819. https://
doi.org/10.1523/JNEUROSCI.6474-10.2011
DUNCAN ET AL.
Tsai, H. H., Li, H., Fuentealba, L. C., Molofsky, A. V., Taveira-Marques, R.,
Zhuang, H., … Rowitch, D. H. (2012). Regional astrocyte allocation reg-
ulates CNS synaptogenesis and repair. Science, 337(6092), 358–362.
https://doi.org/10.1126/science.1222381
Tsai, H. H., Niu, J., Munji, R., Davalos, D., Chang, J., Zhang, H., …
Fancy, S. P. (2016). Oligodendrocyte precursors migrate along vascula-
ture in the developing nervous system. Science, 351(6271), 379–384.
https://doi.org/10.1126/science.aad3839
Ulanska-Poutanen, J., Mieczkowski, J., Zhao, C., Konarzewska, K., Kaza, B.,
Pohl, H. B., … Zawadzka, M. (2018). Injury-induced perivascular niche
supports alternative differentiation of adult rodent CNS progenitor
cells. eLife, 7, 7. https://doi.org/10.7554/eLife.30325
Vallstedt, A., Klos, J. M., & Ericson, J. (2005). Multiple dorsoventral origins
of oligodendrocyte generation in the spinal cord and hindbrain. Neu-
ron, 45(1), 55–67. https://doi.org/10.1016/j.neuron.2004.12.026
van Bruggen, D., Agirre, E., & Castelo-Branco, G. (2017). Single-cell trans-
criptomic analysis of oligodendrocyte lineage cells. Current Opinion in Neu-
robiology, 47, 168–175. https://doi.org/10.1016/j.conb.2017.10.005
Wang, S., Bates, J., Li, X. J., Schanz, S., Chandler-Militello, D., Levine, C., …
Goldman, S. A. (2013). Human iPSC-derived Oligodendrocyte progeni-
tor cells can Myelinate and rescue a mouse model of congenital Hyp-
omyelination. Cell Stem Cell, 12(2), 252–264. https://doi.org/10.1016/
j.stem.2012.12.002
Wang, Y., Cheng, X., He, Q., Zheng, Y., Kim, D. H., Whittemore, S. R., &
Cao, Q. L. (2011). Astrocytes from the contused spinal cord inhibit oli-
godendrocyte differentiation of adult oligodendrocyte precursor cells
by increasing the expression of bone morphogenetic proteins. The
Journal of Neuroscience, 31(16), 6053–6058. https://doi.org/10.1523/
JNEUROSCI.5524-09.2011
Warf, B. C., Fok-Seang, J., & Miller, R. H. (1991). Evidence for the ventral
origin of oligodendrocyte precursors in the rat spinal cord. The Journal
of Neuroscience, 11(8), 2477–2488.
Whittaker, M. T., Zai, L. J., Lee, H. J., Pajoohesh-Ganji, A., Wu, J., Sharp, A.,
… Wrathall, J. R. (2012). GGF2 (Nrg1-beta3) treatment enhances NG2
+ cell response and improves functional recovery after spinal cord
injury. Glia, 60(2), 281–294. https://doi.org/10.1002/glia.21262
Williams, P. R., Marincu, B. N., Sorbara, C. D., Mahler, C. F., Schumacher, A. M.,
Griesbeck, O., … Misgeld, T. (2014). A recoverable state of axon injury per-
sists for hours after spinal cord contusion in vivo. Nature Communications,
5, 5683. https://doi.org/10.1038/ncomms6683
Windrem, M. S., Nunes, M. C., Rashbaum, W. K., Schwartz, T. H.,
Goodman, R. A., McKhann, G., 2nd, … Goldman, S. A. (2004). Fetal and
adult human oligodendrocyte progenitor cell isolates myelinate the
congenitally dysmyelinated brain. Nature Medicine, 10(1), 93–97.
https://doi.org/10.1038/nm974
19
Witte, M. E., Schumacher, A. M., Mahler, C. F., Bewersdorf, J. P.,
Lehmitz, J., Scheiter, A., … Kerschensteiner, M. (2019). Calcium influx
through plasma-membrane nanoruptures drives axon degeneration in
a model of multiple sclerosis. Neuron, 101(4), 615–624 e615. https://
doi.org/10.1016/j.neuron.2018.12.023
Yasuda, A., Tsuji, O., Shibata, S., Nori, S., Takano, M., Kobayashi, Y., …
Okano, H. (2011). Significance of Remyelination by neural stem/-
progenitor cells transplanted into the injured spinal cord. Stem Cells,
29(12), 1983–1994. https://doi.org/10.1002/Stem.767
Yeung, M. S. Y., Djelloul, M., Steiner, E., Bernard, S., Salehpour, M.,
Possnert, G., … Frisen, J. (2019). Dynamics of oligodendrocyte genera-
tion in multiple sclerosis. Nature, 566, 538–542. https://doi.org/10.
1038/s41586-018-0842-3
Young, K. M., Psachoulia, K., Tripathi, R. B., Dunn, S. J., Cossell, L.,
Attwell, D., … Richardson, W. D. (2013). Oligodendrocyte dynamics in
the healthy adult CNS: Evidence for myelin remodeling. Neuron, 77(5),
873–885. https://doi.org/10.1016/j.neuron.2013.01.006
Yuen, T. J., Silbereis, J. C., Griveau, A., Chang, S. M., Daneman, R.,
Fancy, S. P., … Rowitch, D. H. (2014). Oligodendrocyte-encoded HIF
function couples postnatal myelination and white matter angiogenesis.
Cell, 158(2), 383–396. https://doi.org/10.1016/j.cell.2014.04.052
Zai, L. J., & Wrathall, J. R. (2005). Cell proliferation and replacement fol-
lowing contusive spinal cord injury. Glia, 50(3), 247–257. https://doi.
org/10.1002/glia.20176
Zawadzka, M., Rivers, L. E., Fancy, S. P., Zhao, C., Tripathi, R., Jamen, F., …
Franklin, R. J. (2010). CNS-resident glial progenitor/stem cells produce
Schwann cells as well as oligodendrocytes during repair of CNS demy-
elination. Cell Stem Cell, 6(6), 578–590. https://doi.org/10.1016/j.
stem.2010.04.002
Zhang, Y., Chen, K. N., Sloan, S. A., Bennett, M. L., Scholze, A. R.,
O'Keeffe, S., … Wu, J. Q. (2014). An RNA-sequencing transcriptome
and splicing database of glia, neurons, and vascular cells of the cerebral
cortex. Journal of Neuroscience, 34(36), 11929–11947. https://doi.org/
10.1523/Jneurosci.1860-14.2014
Ziskin, J. L., Nishiyama, A., Rubio, M., Fukaya, M., & Bergles, D. E. (2007).
Vesicular release of glutamate from unmyelinated axons in white matter.
Nature Neuroscience, 10(3), 321–330. https://doi.org/10.1038/nn1854
How to cite this article: Duncan GJ, Manesh SB, Hilton BJ,
Assinck P, Plemel JR, Tetzlaff W. The fate and function of
oligodendrocyte progenitor cells after traumatic spinal cord
injury. Glia. 2019;1–19. https://doi.org/10.1002/glia.23706