Review Article

Stem Cell Implants: Emerging Innovation for Stroke Recovery

Reid Colliander1, Kaitlyn Alleman1, Michael Diaz2, Med Jimenez1, Patrick King1, Pranav Mirpuri1, Christopher Cutler1,
Brandon Lucke-Wold3*
1Chicago
Medical School, Rosalind Franklin University, North Chicago, IL, USA
2College
of Medicine, University of Florida, Gainesville, FL, USA
3Department of Neurosurgery, University of Florida, Gainesville, FL, USA

*Correspondence author: Brandon Lucke-Wold, MD, PhD, MCTs, Department of Neurosurgery, University of Florida, Gainesville, FL, USA;
Email: Brandon.Lucke-Wold@neurosurgery.ufl.edu

Abstract
Citation: Lucke-Wold B, et al. Stem Stroke is a debilitating neurovascular injury that those effects hundreds of thousands of
Cell Implants: Emerging Innovation
Americans each year. Despite the high prevalence, disease morbidity and mortality, options for
for Stroke Recovery. J Neuro Onco
stroke intervention and rehabilitation are still limited. Stem cells have shown promise in stroke
Res. 2023;3(1):1-14.
treatment due to their ability to self-renew and differentiate into different cell types. The
https://doi.org/10.46889/JNOR.2023.
3102
primary sources of stem cells used today are bone marrow and fetal brain tissue, with
mesenchymal stem cells, bone marrow stem cells and neural stem cells being particularly well-
studied. By secreting therapeutic and neurogenic substances they are hypothesized to help
Received Date: 03-04-2023
foster recovery at the site of injury. Delivery mechanisms for stem cell therapy include
Accepted Date: 23-04-2023
intracerebral, intra-arterial, intraperitoneal, intravenous, intraventricular and intranasal routes
Published Date: 30-04-2023
with radiographic imaging now being used to monitor the progress of stem cell therapies. Stem
cell implants have been found to be safe but optimal treatment strategies are still being
established with several promising studies underway. Future efforts should continue to focus
on improving efficacy, exploring alternative stem cell sources, enhancing migration capability
Copyright: © 2023 by the authors.
and survival and educating stroke patients on the benefits and risks of stem cell therapy.
Submitted for possible open access
publication under the terms and
Abbreviations
conditions of the Creative Commons
Attribution (CCBY) AART: Action Research Arm Test; BI: Barthel Index; BMSC: Bone Marrow Stem Cell; CNS:
license
(https://creativecommons.org/li
Central Nervous System; CSF: Cerebrospinal Fluid; ESS: European Stroke Scale; EV:
censes/by/4.0/). Extracellular Vesicles; FMA: Fugl-Meyer Assessment; MAPC: Multipotent Adult Progenitor
Cell; MNC: Mononuclear Cell; MRI: Magnetic Resonance Imaging; mRS: Modified Rankin Scale;
MSC: Mesenchymal Stem Cell; MUSE: Multilineage-Differentiating Stress-Enduring Cell;
NIHSS: National Institute of Health Stroke Scale; NSC: Neural Stem Cell; PET: Positron
Emission Tomography; SCT: Stem Cell Therapy; tPA: tissue Plasminogen Activator; UC-MSC:
Umbilical Cord Derived Mesenchymal Stem Cells

Keywords: Stem Cell; Stroke; Exosomes; Neuroregenerative

Introduction
More than 795,000 strokes occur in the United States every year, with nearly 1 in 4 happening in those with a prior history of
stroke [1]. It is estimated that the stroke-related healthcare costs were approximately $53 billion between 2017 and 2018 [1].
Furthermore, stroke is a devastating disease in which survivors frequently experience motor and neurological deficits along with
a decreased quality of life [2,3]. Due to its high prevalence and disease morbidity, the treatment and management of stroke
remains an area of great therapeutic consequence.

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The many varying etiologies of stroke correspond to different treatments which depend largely on the type and timing of the
infarctive event. There are two different subtypes of stroke: ischemic and hemorrhagic. Ischemic strokes result from an occlusion
of the blood supply whereas hemorrhagic stroke is defined by bleeding from a vessel [4]. Ischemic strokes account for
approximately 87% of all strokes and uniquely can be treated with an intravenous injection of tissue Plasminogen Activator (tPA)
[1,5]. This promotes the dissolution of clots and restores patency to the occluded vessel. However, this intervention has a limited
time window and must be administered within 3-4.5 hours of insult [5,6]. Additional therapeutic options include antiplatelet
therapy, which has been shown to be effective at preventing a stroke recurrence within 48 hours but cannot ameliorate the
ischemia that has already occurred [6]. Surgery and other minimally invasive interventions are also used in the setting of ischemic
stroke and include procedures such as mechanical thrombectomy, ventriculostomy and decompressive craniectomy [7,8].
Mechanical thrombectomy is not indicated in all patients and additionally suffers from time constraints as well as it is only
effective up to 24 hours after initial presentation [9]. Unfortunately, there are few treatment options available to address
hemorrhagic strokes. These involve the management of hypertension and raised intracranial pressure, hemostatic therapy and
surgical intervention [10,11]. All of these treatments are largely focused on damage control and preventing spread or worsening
of damage from the inciting event. However, once Central Nervous System (CNS) neurons are damaged, they are for the most
part, unable to regenerate, with no current treatments available intended to renew the damaged neural networks [12]. New
research is hoping to bridge this gap in therapy, with stem cells offering a promise in neuroprotection and neuroregeneration in
the management of stroke.

Research into stem cells is still very much in its infancy. Less than 30 years ago the first primate embryonic stem cell line was
derived from rhesus monkeys and it was only in 1998 that the first human embryonic stem cells were derived by Thomson, et
al., [13,14]. Since then, the field has exploded with a variety of applications scoping many different domains of medicine [15].
There are three classes of stem cells that are being explored in the treatment of stroke. These include neural stem cells, bone
marrow stem cells and mesenchymal stem cells [16].

Mechanism of Action
Stem cells are cells that uniquely have the ability to self-renew and create functional tissues. More specifically, they can
differentiate into nearly any cell type present in the human body, which is what drew scientific interest to their therapeutic
potential in the first place. There are several major categories of stem cells: (1) Totipotent, (2) Pluripotent and (3) Multipotent
[17]. Totipotent cells can form all cell types within the human body, plus the extraembryonic cells that are crucial for early
development of the fertilized embryo. Pluripotent stem cells are commonly used in therapies as they can give rise to all cell types
within the human body. Multipotent stem cells are similar, but more limited in their differentiation potential- these cells include
the adult stem cell and the neural stem cell. Stem cells are further distinct from precursor cells, which are limited to differentiating
into a single cell type and progenitor cells, which cannot divide indefinitely [18,19].

Several mechanisms for the action of stem cells have been proposed over the years. Initially, it was thought that grafted cells
could replace dead sections of the brain and become integrated in their place. This hypothesis has given way to the modern
theory of the bystander effect, wherein implanted cells secrete therapeutic and neurogenic substances that ameliorate injury and
foster regeneration [20,21]. Ever since ischemic stroke was also recognized to impact non-neuronal cell components of the brain
such as glia and vasculature, stem cells are also thought to contribute to angiogenesis, vasculogenesis, anti-apoptosis and anti-
inflammation [22].

Primarily due to its well-established safety in the literature, the bone marrow is the primary source of stem cells in use today
[23,24]. Bone marrow derived populations include Mesenchymal Stem Cells (MSCs), bone marrow stem cells (BMSCs),
Mononuclear Cells (MNCs), endothelial progenitor cells (SB623), Multipotent Adult Progenitor Cells (MAPCs) and Multilineage-
differentiating Stress-Enduring cells (MUSE) [18]. Another primary source of stem cells is human brain fetal tissue, which has
been used to derive important cell lines of Neural Stem Cells (NSCs) [25].

Several initial studies determined the various neuroprotective and neuroregenerative effects of these cells in preclinical and later
clinical settings [26-28]. Based on these trials, MSCs, BMSCs and NSCs are particularly well-studied and promising. For example,
as an autologous cell with determined population purity and well-defined viability and multilineage differentiating potential,

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MSCs have been shown to promote neurogenesis and anti-inflammation, possibly mediated through the secretion of factors
including IL-1, TNF-alpha, IL-11 and TGF-β [20,29,30]. Studies on murine stroke models have also demonstrated the ability of
MSCs to decrease levels of axon growth inhibitors, leading to an increased density of functional axons in the ischemic area [31,32].
BMSCs exert similar mechanisms of action as secreted factors play roles in neurogenesis rather than neuronal replacement.
Unfortunately, neither MSCs or BMSCs studies have led to significant and replicable improvements in neurological outcomes of
stroke patients, but efforts continue. NSCs working through neuroregenerative effects too have shown promise in preclinical
models and there is some data to suggest that implantation of the cell line CTX0E03 has resulted in valid improvements in
functional recovery [33]. Notably, to some extent, all three cell lines have shown the ability to migrate to damaged areas and
even to guide the migration of endogenous cells via “biobridges” of matrix metalloproteinases in-vivo models [34,35]. However,
these clinical studies are very much in early stages of research; efficacious and generalizable criteria for stem cell administration
are still lacking.

The future of stem cell therapies is multifaceted. Naturally, clinical trials with different lineages of cells are underway, but beyond
this classic approach, it has been proposed recently to use derivatives of stem cells such as vesicles, mitochondria, exosomes and
micro-RNAs to foster regeneration in the ischemic area (Fig. 1). These cell components have been shown to exert similar paracrine
effects as compared to stem cells, resulting in neurogenesis and angiogenesis [36,37]. In a similar vein, it has been proposed that
if stem cell therapies are considered as biologics with regards to their paracrine effects, it may be easier to optimize delivery
routes, classify the stem-cell secreted factors and eventually design drugs that mimic these effects [38].

Figure 1: Mechanisms of stem cell therapy include (1) delivery of stem cell derivatives such as extracellular vesicles,
mitochondria and exosomes, (2) direct cell differentiation with replacement and induced migration with "biobridges" and (3)
paracrine secretion of various neurotrophic factors.

Delivery Mechanisms
Unsurprisingly, several different approaches for stem cell delivery exist in the laboratory setting and many have been translated
to clinical settings. Different administration routes have included intracerebral, intra-arterial, intraperitoneal, intravenous,

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intraventricular and intranasal [39]. Stem cells delivered intravenously and intrathecally in stroke patients has led to
improvements in terms of aphasia, motor deficits and spasticity [40]. The advantage of more invasive routes such as intracerebral
is that they allow for a larger number of implanted cells to reach target destinations, but suffer from limited generalizability,
immune rejection and increased risk for infection. On the other hand, less invasive routes such as intravenous do not suffer from
these disadvantages to the same extent and have even shown to have similar effectiveness compared to other delivery methods
to the point that most modern clinical trials prefer to utilize this technique [41,42]. However, one of the major drawbacks of
intravenous stem cell therapy is the pulmonary first-pass effect, meaning the total amount of stem cells injected does not reach
the site of injury. Depending on the type of stem cell, very few reach the target, thus diminishing the therapeutic effect [43]. There
have been recent strides in developing more targeted stem cell delivery methods, not only in terms of reaching the location of
injury but also addressing specific cellular defects following a stroke (Fig. 2).

Extracellular Vesicles (EVs) or exosomes are extracellular membrane-bound vesicles that transmit cargo without direct cellular
contact as a form of intercellular communication [44-46]. EVs have regenerative properties when derived from mesenchymal
stem cells [47]. Different exosome treatments that involve altering genetic properties have improved recovery of the damaged
tissue. For example, miR-542-3p is decreased following stroke in mice models and is thought to play a role in inflammation along
with TLR-4 [48]. An exosome treatment in which miR-542-3p was overexpressed and injected into a mouse stroke model paracele
led to decreased brain injury as well as decreased inflammation [48]. In a similar vein, neural stem cell exosomes treated with
interferon gamma exhibited stronger therapeutic effects in rats when stereotactically transplanted into the area of infarct when
compared to the group receiving the untreated neural stem cell exosomes. Interferon gamma was used to condition the exosomes
due to its ability to improve cell survival in conditions of oxidative stress [49]. Next, rat stroke models administered miR-17-92
cluster-enriched exosomes from mesenchymal stem cells intravenously had increased neurogenesis and neuroplasticity along
with oligodendrogenesis [50]. Further investigation regarding various ways to induce multiple genetic modifications to pre-
condition exosomes may enhance neurorestorative effects.

Much of the current stroke therapy literature turns to EVs as personalized targeted delivery vehicles especially in the application
of stroke where multipotent mesenchymal stromal cells have shown therapeutic effects [51,52]. An important aspect of NSC
therapy is the regulation of NSCs to differentiate into the desired cell fate after transplantation on neural tissue [53-56]. It is
known that many of the stem cells transplanted to the recipient host will commit to the glial progenitor lineage which limits the
therapeutic effects of NSCs in the setting of post-stroke and reperfusion therapy. Although delivery via exosomes may serve to
improve some of the effects of stroke, they are not able to target the site of injury and are therefore limited in terms of their
benefits. Nanoparticle delivery systems are one strategy developed to overcome this. One study involved using iron oxide
nanoparticles-harboring mesenchymal stem cells to enhance delivery to the ischemic lesion in rats. Following systemic injection
into the tail vein, the rats were fitted with a 3D-printed helmet containing a magnet which localized the nanoparticles to the area
of the lesion. This group had enhanced blood vessel density and decreased damage to the neurons in the location of the lesion
[57]. Lin, et al., demonstrated that the utilization of theranostic nanomedicine leads to a 3-4-fold increase in neuronal
differentiation of stem cells that can be detected in vivo with Magnetic Resonance Imaging (MRI) [53]. These findings suggest
the important role of nanomedicine in clinical therapy. Additionally, there is evidence to suggest that mitochondria may serve
as regulators of NSCs which can additionally play a role in targeted gene therapy [58].

Another obstacle has been the differentiation of neural stem cells into astrocytes rather than neurons. The use of
superparamagnetic iron oxide nanoparticles and small interfering RNA/antisense oligonucleotides against Pnky lncRNA in
combination with neural stem cells has shown promise in guiding differentiation into neurons as Pnky lncRNA inhibits neuronal
differentiation [59]. When this system was employed in mice by injecting the stem cells directly into the area of infarct, the infarct
volume was lower than that of mice given neural stem cells without this genetic alteration [53]. Another method for increased
therapeutic effect includes the use of biodegradable polymeric nanoparticles containing adipose stem cells genetically modified
to overexpress vascular endothelial growth factor [60].

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Figure 2: Depiction of two stem cell preparation methods and three delivery routes. The top portion of the figure shows a
method which involves genetically treating exosomes from stem cells prior to delivery. The bottom portion depicts packaging
the stem cells into nanoparticles and the right-hand side of the figure displays three major modes of delivery used in rodent
experiments: intracerebral injection, stereotactic injection and venous injection.

Outcomes Thus Far

The safety of stem cell implants in stroke patients has been well established in several phase 1 and 2 clinical trials [29,30,33,61-
82]. No severe adverse events attributable to stem cell therapy have been reported. Adverse events that have been attributed to
treatment have been minor, transient and primarily due to route of delivery (e.g., headache from intracranial injection)
[29,30,33,61-82].

While no trial has found significant safety concerns, efficacy has been harder to establish. Multiple single arm studies have shown
significant improvements from baseline in a number of measures of stroke burden, including modified Rankin Scale (mRS),
Barthel Index (BI), National Institute of Health Stroke Scale (NIHSS), European Stroke Scale (ESS), Fugl-Meyer Assessment
(FMA), Action Research Arm Test (ARAT) and lesion size [30,33,64,67-70,73,74,79]. For example, Steinberg, et al., followed 18
patients with chronic stroke symptoms (6 months to 5 years) for 2 years after intracranial injection with mesenchymal stem cells
and found improvement from baseline in ESS, NIHSS and FMA that plateaued at 12 months but had not relapsed by the end of
the study [30,70].

Improvement relative to placebos, however, have not been consistent in randomized controlled trials [29,61-63,65,66,71,72,75-
78,80-82]. For example, the ACTIsSIMA trial studied 163 patients using the same cell type and in the same clinical setting as
Steinberg et al., failed to find an improvement in treatment relative to controls (the results are as yet unpublished, but available
on clinicaltrials.gov, trial number: NCT02448641). Other RCTs using intravenous mesenchymal cells in the acute/subacute setting
have had mixed results with improvement in some measures of stroke burden but not others and inconsistency between studies
in which measures show improvement [61,63,66,75,76,78]. Studies investigating CD34+ stem cells have similarly shown mixed
results, with improvement in NIHSS, ESS and mRS with intracranial injection in the chronic setting, but not with intravenous
and subcutaneous injections in the acute/subacute setting [62,65,71,81].

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A recent meta-analysis of randomized trials with scores on the mRS, NIHSS and BI at 6, 12 and 24 months found significant
differences in NIHSS at 6 months and mRS at 12 months that favored treatment [83]. Although differences in the other measures
were not statistically significant, the authors were only able to pool data from four studies (with each analysis containing no
more than three), resulting in only between 50 and 81 patients being analyzed for each outcome. This small overall sample along
with significant heterogeneity between studies (in part due to inclusion regardless of cell type, route and clinical setting) resulted
in wide confidence intervals that, while unable to exclude the null, were still consistent with substantial functional improvement
with treatment [83].

Given the large number of parameters that can vary in this space (cell type, dose, route of delivery, rounds of treatment, time
since stroke onset, etc.), the number of possible best use cases is vast. Different methods may be better suited in the acute versus
the chronic setting and stacking the optimal treatment in each setting may have significant synergistic effects. The established
safety of the treatment, along with the exciting possibilities warrants further study and a number of ongoing trials are doing just
that Table 1 shows trials currently ongoing in this space along with cell type, route of delivery, clinical setting, trial phase, sample
size, trial design and estimated completion date.

Trial/location/acronym Cell Route Setting Phase n Design Estimated Completion Date

NCT05008588 UC-MSC IC acute 1/2 15 RCT-OL December 2023

Indonesia

NCT04811651 UC-MSC IV <6 2 200 RCT-B October 1, 2023

China months
“UMSIS”

NCT05292625 UC-MSC IV/IT <24 1/2 48 RCT-B June 2, 2023

Vietnam months

NCT04631406 NSC IC 6-60 1/2 30 Single Arm December 31, 2024

USA/Canada months

NCT05158101 UC-MSC IV N/A 1 15 Single Arm February 2026

Argentina

NCT04280003 A-MSC IV <4 days 2 30 RCT-B July 15, 2023

Spain
“AMASCIS-02”

NCT01151124 NSC IC 6-60 1 12 Single Arm March 2023

UK months
“PISCES”

NCT04434768 UC-MSC IV/IV+I <36 1 14 Single Arm December 31, 2023

Taiwan A hours

NCT04097652 UC-MSC IV 4-7 days 1 9 Single Arm December 31, 2025

Taiwan

NCT03384433 MSC-CfE IV <24 1/2 5 Single Arm December 17, 2021

Iran hours

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NCT04953663 BM-MSC IV >6 1/2 60 RCT-B January 1, 2023

China months

NCT03545607 APC IV 18-36 3 300 RCT-B June 2023

USA hours

NCT04590118 BM-MSC IV >6 1/2 60 RCT-B August 1, 2023

China months

NCT02795052 BM-MSC IV+IN >6 N/A 500 Single Arm July 2024
UAE months

NCT04093336 BM-MSC IV <7 days 1/2 120 RCT-B August 31, 2024
China

USA = United States of America, UAE = United Arab Emirates, UC-MSC = Umbilical Cord Derived Mesenchymal Stem Cells,
NSC = Neural Stem Cells, A-MSC = Adipose Derived Mesenchymal Stem Cells, MSC-CfE = Mesenchymal Stem Cell Derived
Cell-free Exomes, BM-MSC = Bone Marrow Derived Mesenchymal Stem Cells, APC = Multipotent Adult Progenitor Cells, IC =
Intracerebral, IV = Intravenous, IA = Intraarterial, IN = Intranasal, RCT-OL = Open Label Randomized Controlled Trial, RCT-B =
Blinded Randomized Controlled Trial
Table 1: Ongoing trials.

Radiographic Findings
The promise of stem cell therapies has mandated the study of how cells are trafficked and utilized in the body. In the preclinical
setting, much of this information has come from dissection and analysis of frozen specimens. Imaging as a noninvasive method
of monitoring therapeutic efficacy has been explored more recently. Classically there are two different approaches to tracking
stem cells: direct and indirect labeling with markers such as super paramagnetic iron oxides, perfluoropolyether and
perfluorocarbon which can be picked up by MRI or Positron Emission Tomography (PET) scanning [84]. Several studies have
investigated these techniques, but challenges have included the limitations of spatial resolution of current imaging modalities
and the dynamics of labeling, such as the quantification of tracer uptake and the concentration of tagged cells in a sample [85-
88]. One recent development aimed at managing these challenges is the introduction of reporter genes in stem cells, which when
expressed form molecules that can bind to specific injected radiotracers allowing for easier visualization of stem cell migration
[89].

Neuron-derived EVs regulate the Blood-Brain Barrier (BBB) in both physiological and pathological states [90]. Because EVs can
cross the BBB, they may serve a role when looking for stroke biomarkers or radiological imaging. Some studies already utilize
CD9 or CD63 as a specific marker for EVs that can be fluorescently tagged with GFP in neuroglia and tracked for radiographic
studies [91,92]. Fig. 3 highlights the main functions of exosomes which are being utilized in research as drug therapy vehicles
such as in the setting of stroke. In animal models, Neural Stem Cells (NSCs) in EVs were shown to improve functional outcomes
post-thromboembolic stroke [93]. Exosomes have promising roles in clinical therapy while also allowing for the visualization of
using biomarkers to understand their intercellular interactions and therapeutic effects [45,46].

Radiographic assessment is important for localizing neurological defects and understanding the sequelae of stroke. In acute
settings of suspected stroke, Computed Tomography (CT) can be utilized due to fast imaging speed, wide availability and
production of good contrast between a bright clot and surrounding lower attenuating cortical tissue and Cerebrospinal Fluid
(CSF) [94-96]. MRI can also be utilized but takes longer to obtain imaging [94-96]. In one study, radiographic results administering
EV NSCs in the context of stroke showed decreased infarct volume [93]. This decrease was shown in settings where the EV NSCs
were administered both within and outside the tPA clinical therapeutic window [93]. To elaborate on this finding, other studies
show coupling of angiogenesis and neurogenesis in settings of neurovascular ischemia [97,98]. It is known that when embryonic
stem cells are introduced into rat brains during times of focal cerebral ischemia, these cells can be tracked in-vivo migrating along

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the corpus callosum to reach these ischemic areas from distances as far as the opposite hemisphere [99]. Porcine studies utilizing
EV NSCs also show significant neuroprotection from induced ischemic stroke [100]. MRI results comparing the NSC treatment
group from placebo show at the 84-day mark significant tissue level recovery, decreased cerebral lesion volume and preservation
of white matter integrity [100]. The current research utilizing animal models shows evidence of potential clinical use of NSCs in
the setting of acute ischemic stroke which can be monitored radiographically for spatial and temporal changes.

As discussed in the previous section, initial data regarding clinical Phase I/II trials of the utilization of mesenchymal stem cells
in chronic stroke shows promise. In two of these studies, MRI results showed no progression or new ischemic lesions in the brain
between the delivery of NSCs and prior to discharge [64,101]. Interestingly, one trial showed a reduction of mean lesion volume
>20% at the one-week mark post mesenchymal stem cell infusion as evident on MRI [64]. These early clinical findings show much
promise in the therapeutic utilization of NSCs in the treatment of ischemic stroke.

Figure 3: Exosome function and utilization as nanomedicine. Exosomes are nano-sized (30-150 nm) extracellular vesicles that
transmit cargo to other cells. Much of the recent research utilizes this function to insert drugs and proteins as a form of
regenerative medicine.

Areas Needed for Further Discovery

In the present study, we critically appraised and critiqued the wealth of emerging cell therapy research for stroke recovery.
Though much has been achieved, several areas for focused inquiry and effort have been identified. The most pressing is to
establish the efficacy of Stem Cell Therapy (SCT) as a therapeutic tool, as discussed earlier. However, additional areas for
exploration include developing alternative stem cell sources and wider patient education on SCT.

Intracerebral transplantation of BMSC and MSC implants has demonstrated early promise in promoting the neurogenesis
process post-stroke, but both remain steadily inefficacious relative to NSC implants [18,102]. Current evidence suggests that
further exploration of BMSC and MSC, as well as Umbilical Cord Derived Mesenchymal Stem Cells (UC-MSC), represents a

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worthwhile pursuit in light of their immunomodulatory properties, which may prove clinically valuable for tackling prolonged
post-stroke inflammation states [18,103]. The endogenous repair mechanisms promoted by MSCs have been specifically
attributed to recruitment of immune mediators IL-6 and PGE2 plus responsiveness to IL-1β, which enhances monocyte and
granulocyte recruitment for functional reduction of infarct volume [42,104]. However, despite evidence indicating the safe
implantation of such stem cell populations in human replacement trials, establishing efficacy and best use cases with narrowing
indications is the biggest challenge for future research [18,42,103]. There also exists a surge of early data proposing new
expandable cell lines and methodologies with marked pre-clinical potential for neuropathologies [105-107]. These and the above-
described findings taken together, future stroke research should concentrate efforts on enhancement of stem cell migration
capability and survival within the ischemic environment.

Moreover, patient attitudes and understanding surrounding SCT also represent a much-desired focus area. The available
literature suggests that stroke patients are stratified in their attitudes towards SCT, which may conceivably limit their willingness
to participate in clinical trials or, perhaps worse yet, motivate participation without consideration of the associated risks [108-
110]. Akid and colleagues reported that in a controlled sample of 84 ischemic stroke patients, 12% (10/84) had prior knowledge
of SCT but upwards of 36% (30) reported a willingness to participate in SCT clinical trials after receiving information [108].
Further, they observed that male gender was significantly correlated with positive SCT attitude (OR: 3.74, 95% CI: 1.45-9.61)
[108]. Unsworth, et al., additionally identified younger age, greater perceived caregiver burden and poorer physical functioning,
among others, as strong predictors for considering experimental SCT [110]. It is therefore clear that clinicians must place due
emphasis on educating their SCT candidate populations to appreciate patient perspectives and ensure better-informed consent
protocols in the high-risk neurosurgical arena.

Conclusion
Stroke remains a debilitating and costly sector of the healthcare system with limited options for intervention and rehabilitation.
Due to their unique ability of selective differentiation, stem cells provide a great opportunity to bridge the gap in treatment for
these patients. In-vitro and in-vivo studies have already demonstrated promise in the use of MSC, BMSC and NSC with greater
studies on the horizon. Through the use of exosomes and nanoparticles, intravenous and intrathecal delivery of stem cells may
soon provide therapeutic benefit to those suffering from cognitive and neurological impairments following a stroke.

Acknowledgements
We would like to acknowledge BioRender.Com for allowing us to use their software to generate all of the images and figures
displayed in this review.

Conflict of Interest
The authors have no conflict of interest to declare.

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