Literature Review INAMSC Competition 2018

The Potential of Mesenchymal Stem Cell to Repair Retinal Cell Damaged caused by
Glaucoma

M YusanPratama*, Kaharudin**, Hendi Rinaldi***

* Third Year Medical Student, UniversitasAndalas, (yusan.pratama@gmail.com)(id

line:pram030597, phone number :082388304973)

** Third Year Medical Student, UniversitasAndalas, (kaharrudin@gmail.com)

*** Third Year Medical Student, UniversitasAndalas, (hendirinaldi@gmail.com)

Abstract

Glaucoma is The third major cause of blindness worldwid after cataract and
uncorrected refractive error. Prevalance of glaucoma estimate will increase until 111.8
million in 2040,this estimating is important to look for promising glaucoma treatment. The
only proven method to treat glaucoma is focus to reduction of intraocular pressure with
ocular hypotensive drops, laser trabeculoplasty and surgery. However these treatment not
fully repair the blindness. Stem cells are a type of cell that have high self-renewability and
differentiation which potentially used as cell replacement therapy. To avoid stem cell
rejection during transplantation, the research focus to stem cells isolated from multipotent,
adult stromal cells, as known as MSCs. Looking for ethical concern about MSCs, it can be
found abundantly in adult and fetal tissue such as bone marrow, adipose tissue, umbilical
cord, placenta, and amniotic tissue. The MSCs have pottential to repair retinal cell damaged
that caused by glaucoma through mechanism such as differentiation to demaged cell,
paracrine action, modulation of host’s immune responses at inflamed site, and anti-
angiogenic trophic action in certain ocular disorder. In order to exploring possible alternative
therapy to repair retinal cell, Mesenchymal Stem Cells (MSCs) may prove to be a promising
therapy.

Keyword: Glaucoma, Mesenchymal Stem Cell, Retinal Cell, Stem Cell therapy

Introduction ocular hypotensive drops, laser

Recently glaucoma is The third major
cause of blindness worldwid after cataract
and uncorrected refractive error1. The
blindness related to degeneration of retinal
ganglion cell by high level of intraocular
pressure and the other factors that may
also play a role2.
Prevalance of glaucoma estimate will
increase until 111.8 million in 2040,this
estimating is important to look for
promising glaucoma treatment3. The only
proven method to treat glaucoma is focus
to reduction of intraocular pressure with
trabeculoplasty and surgery2. However
these treatment not fully repair the
blindness.
Stem cells are a type of cell that have high
self-renewability and differentiation which
potentially used as cell replacement
therapy6. Therapy for repair retinal
damaged focus on improving the cell
recovery and regeneration retinal neuron
cell through stem cell by genetic,
chemical, or mechanical manipulation7.
Looking for ethical concern about MSCs,
it can be found abundantly in adult and
fetal tissue such as bone marrow, adipose
tissue, umbiical cord, and placenta,
amniotic tissue8,9. In order to exploring
possible alternative therapy to repair
retinal cell, Mesenchymal Stem Cells
(MSCs) may prove to be a promising
therapy.
Methods
Reviewer collect articles and journals on
scientific sarch sites, pubmed, and google
scholar with keywords glaucoma,
mesenchymal stem cell, Retinal cell. The
materials are selected throught skrinning
abstract and reading other review articles
until we found and selected about 59
journals that use ini this literatur review.
Result and Discussion
Glaucoma Complication
The word “glaucoma” was derived from
Greek (Glaucosis) during hippocratic era
in 400BC that has meant the greenish
pupillary hue in eye which is much
different from the normal pupillary color10.
Process in glaucoma involve imbalance
between secretion of aqueous humor by
cilliary body and its drainage, this process
will determine intraoculer pressure in tha
eye (figure 1).
Intraocular pressure from glaucoma can
cause mechanical stress and strain on
posterior structure of the eye specially
lamina cribrosa and adjacent tissues
(figure 2)11.
Mesenchymal Stem Cell
Administration of MSCs have revealed
potentially can restoration of the visual
system (figure 3). The MSCs therapeutic
mechanism involving (i) cell
differentiation processes to replace loss or
demaged cell, (ii) paracrine action for cell
repair and revival, (iii) modulation of
host’s immune responses at inflamed site,
(iv) anti-angiogenic trophic action in
certain ocular disorder (figure 4)17,18,19.
Bone marrow is the first isolation source
of MSCs following by umbilical cord and
adipose tissue. Although bone marrow is
the best source of obtaining MSCs, there
are some aspects that reduced their use:
Limited growth rate, differentiation
capability depending on the donor age, and
risk inherited to sample collection20.
Figure 1. Aqueous Humor Drainage Pathway of Healthy and Glaucomatous Eyes.

Figure 2. Schematic Illustration of Normal Anatomy and Neurodegenerative Change Associated with
Glacomatous Optic Neropathy
Figure 3. A schematic of Mesenchymal Stem Cells (MSCs) administration from different
sources as therapeutic strategies in retinal degenerative diseases. Multiple routes of
administration including subretinal, intravitreal, intraocular, epiretinal or subtenon injections
can be implemented to deliver MSCs into the posterior lining of the eye.

Figure 4. The signaling pathways involved in MSC-mediated therapeutic strategies in the

eye.
 Figure 5. A timeline representation of strategies used to direct human MSCs differentiation
into retinal neurons and retinal pigmented epithelial cells, in vitro.
MSC and Its Differentiation Potential
Investigations have reported the in vitro
and in vivo regenerative potential of
MSC into endodermal and ectodermal
lineage23,24. This phenomenon is referred
to either dedifferentiation or trans-
differentiation processes25. De-
differentiation is an innate regenerative
activity that reverse a differentiated cell
into undifferentiated progenitor cell of the
same lineage. Meanwhile, trans-
differentiation is two differentiation
process that involves the dedifferentiation
of terminally-differentiated cells and
subsequent differentiation into specialized
cells of a different lineage26.
A figure shows various protocol on MSCs
of different origins to direct cell
differentiation into retinal-like lineages,
including photoreceptors and RPE cells
(Figure 5). MSCs can be induced to
differentiate with taurine or VIP days or
through a combination of selective
induction cocktails comprised of Dkk-1,
Noggin, bFGF, and IGF 1, taurine, HPL,
and β-ME or nicotinamide and activin A.
Using a different protocol on MSCs with
similar source can develop into retinal
neurons or RPE as early as 8 days until 63
days27-31. The potential of MSCs
differentiate into the desired cell is
difference depand on the presence of “rare
cell” that fill the residential MSCs niche,
also termed as multilineage-differentiating
stress-enduring (MUSE) cells, in which
they represent the subpopulation of
successfully differentiated MSCs 33.
MUSE cells are pluripotent somatic stem
cells that are found tied to the fibroblasts
or MSCs of all tissues or organs, These
cells displayed an efficiency differentiation
into multigerm lineages of mesodermal,
endodermal, and ectodermal, and devoid
differentiation into teratoma formation34.
Paracrine Activity of MSCs Aids Retinal
Cell Repair and Revival
The field has made particular progress in
defining several other mechanisms of
administered MSCs can promote tissue
rescue/repair include paracrine activity
that involves secretion of proteins/peptides
and hormones and transfer of exosomes or
microvesicles containing RNA and other
molecules. Recent study was provided
visual improvement with profound
photoreceptor cell survivability in rat
retina. MSCs released trophic peptides
that can stimulate phagocytic activity of
RPE on lethal photoreceptors
35
remnants . MSC also reduce damage in
posterior lining of the eye and induce cell
regeneration by paracrin release of
Hypoxia-Inducible Factor-1α (HIF-1α) and
axonal Growth-Associated Protein-43
(GAP–43), respectively9. Another study
also found that MSC can also exerted
protective action in axotomized rat RGCs
and promoted neurite formation by
releasing other paracrin release of
Prostaglandin E2 Receptor (PGE2R) and
IL-6-mediated growth factors, such as
Platelet-Derived Growth Factor (PDGF)
and Nerve Growth Factor (NGF)36.
Another trial reported the neurotrophic
factors, such as NGF, bFGF, and Glial Cell
Line-Derived Neurotrophic Factor
(GDNF) can preserve retinal ganglion cell
survivability and reduced oxidative stress
damage in the retina35.
Beside the secretory cytokines, increasing
evidence reported to therapeutic potential
of extracellular vesicles released from the
MSCs believed play a crucial role in
modulating cell-to-cell communication in a
paracrine manner37,38,39. It also identified
that intravitreal delivery of exosomes-
derived from MSCs (the classified of
exstacelluler vesicle ) exhibited restorative
and protective actions in mouse models of
retinal injury40.
MSC reduces inflammation in glaucoma
One that causes glaucoma is the immune
system dysregulation41. it is proved by a
profound release of pro-inflammatory
cytokines, Matrix Metalloproteinases
(MMPs), chemokines, that progressively
results in destruction and leakage of BRB
(blood-retinal barrier), the loss of
endothelium tight junction proteins that
facilitating the infiltration of immune
cells42. they will trigger antigen-activated
Cluster of Differentiation 4 (CD4) T cells
to release some essential factors such as
IL-21, IL-6, IL-23, and Transforming
Growth Factor-β (TGF-β) for Th17 cells
and Interferon-γ (IFN-γ) and IL-12 for T
helper type 1 (Th1) cells. All of these
conditions will cause more severe
glaucoma43.
The eye is special organ manifesting
immune privilege (IP) in which immune
responses to foreign antigens. This is
evidenced by the eyes have parenchymal
cells- especially from the ciliary body, iris,
and RPE (Retinal-pigmented epithellial)
cells that can . Another study also prove
that MSCs releasing of neurotrophic
action of Ciliary Neurotrophic Factor
(CNTF) and Brain-Derived Neurotrophic
Factor (BDNF) secreted from MSCs in an
oxidative-induced RGCs culture can
decrease pro-inflammatory cytokines, such
as Tumor Necrosis Factor-α (TNF-α) and
Interleukin-1β (IL-1β)45.
The authors reported improved survival of
RGCs after intravitreal MSC transplant
based on an experimental study of
glaucomatous mouse models50.
Successfully integrated MSC is found to
be in the ganglion cell layer and INL, in
which they affect the host immune
response by suppressing the production of
proinflammatory cytokines for interferon-γ
a aand TNF-α through activation of IL-1
IL-1 Receptor (IL-1RA) and PGE2R51.
MSCs Modulates Angiogenic Activity in
Glaucoma
One of the manifestations of glaucoma that
can cause blindness is a massive
angiogenesis process by sprouting of new
blood vessels from the existing vessels52.
This angiogenesis process results from the
release of angiogenic factors by RPE and
retinal cells53. Untreated conditions in
patients can cause neovascularization with
the functional impairment effects of
neurosensors in the retina54. VEGF
(vascular endothelial growth factor) is the
most studied proangiogenic factor
implicated in the neovascular glaucoma
pathogenesis55. VEGF plays an important
role in mediating active intraocular
neovascularization in patients with retinal
ischemic disease. VEGF is usually
released after retinal ischemia, and spreads
through the aqueous humor into the
anterior segment of the eye resulting in
neovascularization of iris, iridokornea
angle, and connective tissue membrane.
Then, followed by sinecia from the
peripheral iris and trabecular meshwork,
which leads to increased IOP and even
blindness56.
One potential of MSCs to therapeutic
effect is to modulate ocular neovascular
activity. In an oxygen-induced retinopathy
mouse model, intraperitoneal
transplantation of human placental
amniotic membrane-derived MSCs
efficiently homed to and engrafted onto
the injured site with profound release of
angiogenic factor, Transforming Growth
Factor-β1 (TGF-β1) from MSCs.
Astonishingly, upregulation of TGF-β1
level significantly decreased endothelial
cell proliferation devoid of
neovascularization while restoring retinal
angiogenesis57. It has been shown that
TGF-β1 signaling inhibits EC (endothelial
cells) proliferation and migration58, and an
in vitro study showed that coculture of
pericytes and endothelial cells induces
secretion of activated TGF-β1, which in
turn promotes vascular cell
Conclusion
The MSCs have pottential to repair retinal
cell damaged that caused by glaucoma
through mechanism such as differentiation
to demaged cell, paracrine action,
modulation of host’s immune responses at
inflamed site, and anti-angiogenic trophic
action in certain ocular disorder.
Improved understanding of MSC function
holds great promise for the application as
cell therapy and also for the development
of powerful cell-derived therapeutics for
regenerative medicine.
Conflict of Interest
It will takes high cost to implement the
stem cell in Indoneisa, because indonesia
only has viewer skilled worker for doing
that and the tecnology for it still
developed.
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