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Received: 29 August 2018
|
Accepted: 15 November 2018
DOI: 10.1002/jcb.28207
PROSPECTS
Stem cell‐based cell therapy for neuroprotection in stroke:
A review
Reza Rikhtegar
1
|
Mehdi Yousefi
2,3
|
Sanam Dolati
1,4
|
Hosein Delavar Kasmaei
5
|
Saeid Charsouei
1
|
Mohammad Nouri
2
|
Seyed Kazem Shakouri
1,6
1
Aging Research Institute, Tabriz
University of Medical Sciences,
Tabriz, Iran
2
Stem Cell Research Center, Tabriz
University of Medical Sciences,
Tabriz, Iran
3
Department of Immunology, School of
Medicine, Tabriz University of Medical
Sciences, Tabriz, Iran
4
Student's Research Committee, Tabriz
University of Medical Sciences,
Tabriz, Iran
5
Department of Neurology, Shohada‐e‐
Tajrish Hospital, Shahid Beheshti
University of Medical Sciences,
Tehran, Iran
6
Physical Medicine and Rehabilitation
Research Centre, Tabriz University of
Medical Sciences, Tabriz, Iran
Correspondence
Mehdi Yousefi, PhD, Assistant Professor
of Immunology, Department of
Immunology, Faculty of Medicine, Tabriz
University of Medical Sciences, Tabriz,
Iran.
Email: Yousefime@tbzmed.ac.ir
Seyed Kazem Shakouri, M.D. Professor,
Department of Physical Medicine &
Rehabilitation, Tabriz University of
Medical Sciences, Tabriz, Iran.
Email: shakourik@tbzmed.ac.ir
Funding information
Aging Research Institute, Tabriz
University of Medical Sciences
Abstract
Neurological disorders, such as stroke, are triggered by a loss of neurons and glial
cells. Ischemic stroke remains a substantial problem for industrialized countries.
Over the previous few decades our understanding about the pathophysiology of
stroke has enhanced, nevertheless, more awareness is required to advance the field of
stroke recovery. Existing therapies are incapable to adequately relief the disease
outcome and are not appropriate to all patients. Meanwhile, the majority of patients
continue to show neurological deficits even subsequent effective thrombolysis,
recuperative therapies are immediately required that stimulate brain remodeling and
repaironcestrokedamagehashappened.Celltherapyisemergentasahopefulnew
modality for increasing neurological recovery in ischemic stroke. Numerous types of
stem cells from various sources have been identified and their possibility and
efficiency for the treatment of stroke have been investigated. Stem cell therapy in
patients with stroke using adult stem cells have been first practiced in clinical trials
since 15 years ago. Even though stem cells have revealed a hopeful role in ischemic
stroke in investigational studies besides early clinical pilot studies, cellular therapy in
human is still at a primary stage. In this review, we summarize the types of stem
cells, various delivery routes, and clinical application of stem cell‐based therapy for
stroke treatment.
KEYWORDS
clinical trials., ischemic stroke, stem cell therapy
1
|
INTRODUCTION
Stroke is one of the most common causes of the death,
after cancer and myocardial infarction and happens
mainly in the old population with a higher risk in men.
1
Reports indicate that the morbidity and mortality of
stroke have increased during previous decades.
2
Globally,
stroke is in second or third place of mortality list and the
fifth principal reason of death in the United States.
3
Stroke is triggered by stumbling block of a cerebral artery,
leading to focal ischemia, loss of neurons and glial cells,
causing motor, sensory, or cognitive injuries. Two
J Cell Biochem. 2018;1-14. wileyonlinelibrary.com/journal/jcb © 2018 Wiley Periodicals, Inc.
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1
foremost types of stroke are known: Hemorrhagic and
ischemic stroke.
4
Hemorrhagic stroke happens as soon as
rupture of blood vessels in the brain, whereas ischemic
stroke occurs following embolism, thrombolysis, or
cryptogenic mechanisms in which blood supply to the
brain is disturbed and is described as the main type of
ischemic stroke (87%).
5
Ischemic stroke happens when
an area of brain tissue is underprivileged of oxygen
supply because of a reduction in local blood flow. The
normal function of the brain ends if oxygen deprivation
exceeds 60 to 90 seconds and brain tissue death happens
within 3 hours of anoxia leading to cerebral infarction.
5,6
The severe injury to the brain tissues following ischemic
stroke contains not only devastation of a heterogeneous
population of brain cell types, but also main damage of
neuronal networks and vascular systems.
7
It has been
known that brain ischemia motivates neurogenesis by
stimulating neuronal migration through the damaged
area via secretion of neurotrophic factors such as brain
derived neurotrophic factor (BDNF), vascular endothelial
growth factor (VEGF), cytokines like monocyte chemoat-
tractant protein (MCP‐1), and macrophage inflammatory
protein (MIP‐1).
5
Even though there are developing
treatments that repair perfusion to the ischemic brain,
containing tissue plasminogen activator (tPA), a throm-
bolytic agent, can only be administered during the acute
onset of stroke pathology,
8
along with intra‐arterial/
endovascular processes to re‐canalize blood vessels.
These types of treatment reported to decrease stroke
mortality.
9,10
Currently, the only confirmed therapy for
ischemic stroke is thrombolysis, which must be applied
within 4.5 hours after attack.
11
However, due to hemor-
rhagic problem, thrombolysis is still not commonly
practiced.
12
Furthermore, accessible surgical interven-
tions aim to decrease the general risk of clot formation
during stroke.
13
Neurological injury as a consequence of
ischemia is in principal permanent, thus it is essential to
progress innovative therapeutic attitudes to recover
missing neurological functions over the renewal of
neurons.
14
Available treatment possibilities for patients
with ischemic stroke are limited. Therefore, the perfect
cell‐based therapies should not only directed towards
replacement of missing cell types, renovation of func-
tional, and suitable neuronal networks, but also the
rebuilding of disturbed vascular systems.
15,16
Human
cells should be capable of substituting dead neurons,
remyelination of axons, and repair of injured neural
circuitries.
17
This review presents the most current
improvements in stem cell therapy applied for ischemic
stroke, aiming to evaluate its safety and efficiency profile
with emphasis on embryonic stem cells (ESCs), me-
senchymal stem cells (MSCs), and neural stem cells
(NSCs).
2
|
PATHOPHYSIOLOGY OF
ISCHEMIC STROKE
After an ischemic stroke, neurons are left without oxygen
and energy whereas, energy‐dependent processes in neuro-
nal cells are greatly affected.
18
Instantly following ischemia,
neurons fail to maintain their normal transmembrane ionic
gradient and homeostasis properties.
19
This phenomena
could induce numerous processes causing the cell death,
such as excitotoxicity, mitochondrial dysfunction, inflam-
mation, and oxidative and nitrative stress, because of a great
intracellular influx of Ca
2+
ions subsequent disruption of
transmembrane protein channels. Moreover, production of
reactive oxygen species (ROS) upregulated by Ca
2+
influx in
the mitochondria implicated in reperfusion damage after
ischemia leading to necrosis.
20
In addition, due to a
disruption in the ionic gradients following ischemia,
availability to nutrients required for neuronal cells is
reduced which leads the overproduction of excitatory
amino acids such as glutamate.
21-23
N‐methyl‐D‐aspartate
(NMDA) glutamate receptor prompts augmented amounts
of intracellular Ca
2+
influx and leads the activation of Ca
2+
‐
dependent enzymes comprising proteases, calpain, and
caspases dependent cellular death pathways containing
caspase‐12, caspase‐9, and caspase‐3 after the release of
cytochrome C, thereby setting off mitochondrial mechan-
isms of apoptosis and necrosis.
24
Dying neural cells could
release signals to activate proinflammatory pathways
leading to post ischemic inflammation that plays a role to
trigger the immune response. Both pro‐and anti‐inflam-
matory mediators are described to implicate in the
pathogenesis of ischemic stroke.
25
Inflammatory cells are
contributed to ischemic stroke‐related inflammation; pro-
cedures that are associated with the act of interleukin‐17A
(IL‐17A).
7
In the cerebrospinal fluid (CSF) of patients in the
acute period of ischemic hemispheric stroke, proinflamma-
tory cytokines are raised; while, protective anti‐inflamma-
tory and trophotropic factors are reduced, which may
stimulate an inflammatory response after ischemic stroke.
25
3
|
STEM CELL‐BASED
THERAPIES
Stem cells are undifferentiated cells capable of self‐
renewal and proficient of differentiation into multiple
cell types. Stem cell therapy has gained consideration
increasingly as a treatment of unmanageable disorder
such as ischemic stroke,
26
possibly by secreting various
neural trophic factors, immunomodulation, neuroprotec-
tion, angiogenesis, and maybe also prompting neuronal
replacement.
27
The first aim of implementing stem cells
to treat ischemic stroke was to renew the stroke‐impaired
2
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RIKHTEGAR ET AL.
tissue using cellular replacement. Locally injection of
cells to the ischemic area has shown to be more effective
than the intravenous perfusion.
28
Amazingly, various
investigators established that nearly 80% of transferred
cells die 3 days post transplantation, due to the
antagonistic microenvironment of the lesion site.
28
Transplantation of stem cells, causes the immune
response,
29
and immune rejection is still a main draw-
back mostly in the clinical studies of neurological
disorders in which immune suppression is part of the
clinical procedure protocol.
30
Use of biocompatible and
biodegradable biomaterials including Alginate, Dextran,
And Hyaluronan/methyl cellulose (HAMC), in which are
not generate major immune response, is a hopeful
attitude for facilitation of the effectiveness of trans-
planted stem cells in stroke treatment. Numerous clinical
trials investigating the effect of stem cell therapy for
stroke patients are being conducted. The outcome hope-
fully will provide indication on the therapeutic effect of
cell transplantation, however, the effectiveness of stem
cell therapy in greater numbers of stroke patients is yet to
be confirmed.
31,32
Schematic presentation of stem cell
therapy in stroke is illustrated in Figure 1.
3.1
|
Embryonic stem cells
Embryonic stem cells (ESCs) are pluripotent cells
retrieved from the internal cell bulk of human blasto-
cysts, the inner cell mass (ICM). ESCs have the strong
ability to limitless self‐renewal further discriminate into
cells of all three germ layers, that is, endoderm,
mesoderm, and ectoderm.
33
In particular settings, after
administration of fibroblast growth factor‐2 (FGF‐2),
ESCs could be differentiate into neural lineage cell
types.
34
The differentiated neural cells have been
reported to express glutamatergic, GABAergic, or dopa-
minergic markers.
34
Human‐derived ESCs have been
broadly investigated during current years for generation
of different types of neurons.
35,36
ESCs‐derived mesench-
ymal stem cells, vascular progenitor cells, and neural
progenitor cells have been revealed to provide valuable
effects without visible tumorigenesis.
37,38
Neuronal pro-
genitor cells derivative from ESCs are capable of
decreasing infarct volume, rendering neurogenesis, and
improving developmental behavior.
39
Transferred em-
bryonic neural stem cells are able to motivate angiogenic
cytokines, through vascular endothelial proliferation
within 15 days post cerebral ischemia.
40
To date no
FIGURE 1 The schema picture of stem cells therapy in brain stroke. Stem cells separated from various source tissues and proliferated,
differentiated or genetically modified in in vivo environment. In the second stage stem cells administrated in various routes such as
intravenous, intrathecal, and intraperitoneal. Finally, this stem cells induce their therapeutic effects in different manners; 1. Direct
differentiation to neuron, oligodendrocyte, and astrocyte. 2. Stimulation of angiogenesis. 3. Stimulation of synaptic plasticity and new
synaptic formation. 4. Stimulation of endogenous neurogenesis. NSC migration and proliferation. BM; bone marrow. UCB; umbilical cord
blood. AD; adipose tissue. HSC; hematopoietic stem cell. ESC; embryonic stem cell. MSC; mesenchymal stem cell. iPSC; induced pluripotent
stem cell. NSC; nero stem cell. CNS: central nervous system. IV, intravenous; IT, Intrathecal; IP, Intraperitoneal
RIKHTEGAR ET AL.
|
3
clinical trials have been implemented on the use of ESCs
for stroke treatment. Objections such as ethical concerns,
heterogeneity of donor cells, immunological response,
and restricted accessibility of ESCs, restrict their possible
usage for clinical applications. Nevertheless, more basic
and preclinical experimentation should be performed to
understand the possible clinical applications of ESCs.
40,41
3.2
|
Mesenchymal stem cells
Mesenchymal stem cells (MSCs) are multipotent cells,
derived from bone marrow, heart and adipose tissue,
placenta, and skeletal muscle, which are generally
scattered in the entire body and are comfortable to
isolate, with the exceptional capability to differentiate
into mesodermal, endodermal, and ectodermal cell types,
including neurons.
42,43
MSCs are proficient to cross the
blood‐brain barrier (BBB) and specially migrate to the
injured sites, slow down the apoptosis process, raise basic
fibroblast growth factor, and stimulate endogenous
cellular proliferation.
44
The extensive accessibility of
MSCs, creates them a worthy cell candidate for ther-
apeutic approaches concerning stroke.
45
Transplantation
of MSCs into middle cerebral artery occlusion (MCAO) of
stroked rats has been reported to cause the motor
recovery through enhancing of the angiogenesis, and
upregulation of cellular plasticity.
46
MSCs could further
stimulate stroke recovery through mediation of secretion
of neurotrophic factors, such as brain derived neuro-
trophic factor (BDNF) and also lead to secret the
angiogenic mediators.
47
Systemic or peripheral adminis-
tration of MSCs have been reported as a safe and
operative practice for stem cell transplantation.
48
Intra-
venous administration of allogenic MSCs has been
confirmed functional for recovery following stroke.
49
MSCs can be obtained from various peripheral tissues of
an individual. Therefore, autologous MSCs are another
probable source of stem cells that produce a minus severe
immune reaction subsequent transplantation.
50
While
use of autologous MSCs is the method of select to guard
against immune rejection, the elongated time frame
required to attain adequate numbers of MSCs from the
patient's own tissue, makes the usage of “off‐the‐shelf”
allogeneic MSC therapy more suitable.
51
3.3
|
Neural stem cells
Neural stem cells (NSCs) play a significant role in brain
homeostasis and have been known to imply therapeutic
activities subsequent neurovascular damage.
52
NSCs may
be derived from embryonic, fetal, or adult brain and have
the capability to form all cell types necessary to advance
neurological function.
27
NSCs transplantation is an
efficacious therapy for ischemic stroke over numerous
mechanisms, such as maintenance of the BBB, lessening
of neuroinflammation, increased neurogenesis and angio-
genesis, and eventually practical neurological recovery.
53
Human neural progenitor cells (hNPCs) derived from
embryonic and fetal tissues, have the capability to create
neurons, astrocytes, and oligodendrocytes, as well as
integrating to the host tissue and establish neuronal
features, such as synapse formation, expression of synaptic
proteins, and electrophysiological properties.
54
Brain
ischemia could increase endogenous hNPCs and occa-
sionally induce differentiation into the principal cell types
of the damaged site.
55,56
Furthermore, neuroinflammation
subsequent ischemic stroke is competent to prompt NSCs
enrollment.
57,58
Other possible strategies to rise endogen-
ous NPCs proliferation is administration of hormones such
as erythropoietin, and anti‐inflammatory drugs such as
indomethacin.
59
Stem cells function as a local or systemic
immunoregulatory machinery and could motivate the
recovery after stroke through diminishing inflammatory
molecules.
60
hNPCs might improve post‐stroke plasticity
by enhancing of synapse creation, dendritic branch off,
and axonal connections.
61
3.4
|
Other stem cells
3.4.1
|
Induced pluripotent stem cells
Induced pluripotent stem cells (iPSCs), are another
source of stem cells and express four critical factors, that
is Oct3/4, Sox2, c‐Myc, and Klf4.
62
Human induced
pluripotent stem cells (hiPSCs) encourage possible
restorative abilities after ischemic stroke over their
neuroprotective and neurodegenerative features.
63
Dur-
ing recent years, iPSCs have gained increasing attention
as an interesting cell source for reparation of neuronal
network disturbed by ischemic stroke, however, the
tumorgenicity of grafted iPSCs is still a serious pro-
blem.
64,65
iPSC‐derived tumors have shown to have
higher expressions of phosphorylated vascular endothe-
lial growth factor receptor‐2(p‐VEGFR‐2) and matrix
metallo proteinase‐9 (MMP‐9), which might be involved
in stimulating the teratoma creation.
66
Human fibroblast‐
derived iPSCs grafted to rats subsequent MCAO stroke
transfer to the injured zone and partly reinstate
sensorimotor function.
67
Promptly, proliferation, and
multipotential differentiation of iPSCs imply that these
type of potent cells could be very hopeful after stroke
complications.
67
Considering the pros and cons of
application of iPSCs as an autologous source for patients
with stroke, there are numerous factors which requisite
to be taken into account. First, the risk for stroke in 75 to
84 years old is 25‐fold higher than 45 to 54‐years‐old
people.
68
Second, the vast majority of stroke patients are
4
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RIKHTEGAR ET AL.
older than 75 years, so generation of iPSCs from aged
sources would be challenging. And finally, the effective
generation and expansion of iPSCs from an aged patient's
skin fibroblast cells based on present technologies is not
possible.
69
Generation of well‐characterized iPSCs toward
desired a neuronal phenotype, with adequate number
required for transplantation might take at least 7
weeks.
63,69,70
It is possible that the most appropriate time
for transplantation after stroke in humans will be from
several weeks up to 3 months.
70
iPSCs can make available
immune reaction‐free and specially tailored stem cell
therapy.
29
The administration of iPSCs derived from the
somatic cells of the transplant recipient, could overcome
the immune reaction.
71
Establishment of iPSC banks has
been considered in numerous countries such as Japan,
the United States, and the United Kingdom. The most
advanced iPSC bank is located in Japan and by 2022 is
expected to have about 60 iPSC lines covering all human
leukocyte antigen haplotypes for the entire population of
Japan.
72
3.4.2
|
Hematopoietic stem cells
Hematopoietic stem cells (HSCs) are another class of
stem cells derived from bone marrow, and are capable to
differentiate into red blood and lymphoid cells.
73
Administration of HSCs has been reported to diminish
the ischemic infarct volume at cerebral cortex of the
MCAO stroke model.
74
Application of HSCs in existence
of stem cell factor (SCF) and granulocyte‐colony stimu-
lating factor (G‐CSF) in the hypoxia‐ischemia model,
reduced atrophy in the ipsilesional cerebral hemi-
sphere.
75
These results imply that HSCs are possibly
valuable stem cells source and valuable candidate for
improving ischemic stroke motivated degeneration.
75
3.4.3
|
Bone marrow stromal cell
Bone marrow stromal cell (BMSCs) express a wide‐range
of angiogenic/arteriogenic cytokines such as placental
growth factor (PIGF), basic fibroblast growth factor 2
(bFGF/FGF2), vascular endothelial growth factor
(VEGF), insulin‐like growth factors (IGFs), and angio-
poietin 1(Ang‐1),
76,77
that involved in brain plasticity and
retrieval of neurological function following stroke.
78
3.4.4
|
Human umbilical cord blood cells
Human umbilical cord blood cells (HUCBCs) could
mainly differentiate to neurons and a minor group could
differentiate to astrocytes. HUCBCs are consist of
mesenchymal stem cells which differentiate to neural
cells, and also contain a big amount of hematopoietic
colony‐forming cells.
79,80
Systemic administration of
CD34+ cells derived from HUCBCs following stroke
stimulated angiogenesis and neurogenesis, and developed
behavioral recovery.
81
Administration of HUCBCs sub-
sequent cerebral ischemia has been known to reduce
neuroinflammation
82
through enhancing the production
of IL‐10 and reducing of interferon‐γ(IFN‐γ), so causing
repression of T‐cell proliferation.
83
Primary intravenous
treatment with HUCBCs at 24 hours after MCAO,
improved functional recovery and cell migration, there-
fore, seems to be optimum for clinical treatment of
stroke.
84,85
Although cord blood is introduced as a good
source for cell‐based therapies, however, its application
and safety is yet to be confirmed.
86
3.4.5
|
Endothelial progenitor cells
Endothelial progenitor cells (EPCs) are commonly
produced and sustained in bone marrow and could be
transferred into the injury site and contribute into blood
vessel remodeling and repair.
87
Current studies illu-
strated that EPCs transplantation prompted focal angio-
genesis and neurogenesis, improved cerebral blood flow,
diminished neuronal cell death, decreased infarct vo-
lume, and enhanced neurobehavioral retrieval after
ischemia.
87,88
These features of EPCs imply their
therapeutic prospective for treatment of cerebral ische-
mia, and might contribute to blood vessels formation and
release of paracrine trophic factors.
89
In the case of
stroke, different types of cell transplantation, such as
NSCs, MSCs, iPSCs, BMSCs, and HUCBCs have been
described to reduce postischemic inflammation.
90,91
Achieving the mature neuronal phenotype seems to
depend on the source of the stem cells 30% of ESCs, 2% to
20% of MSCs, 34% to 60% of NSCs, 40% to 66% of iPSCs,
and 16.8% of BMSCs could differentiated into neurons.
16
4
|
CELL DELIVERY ROUTES
The effectiveness of stem cell therapy is considerately
linked to the route and location of grafting. Intrapar-
enchymal cell transplantation have shown intense side
effects containing motor deteriorating, syncope, seizures,
and chronic subdural hematoma.
92
In intracerebroven-
tricular delivery, some stroke patients have fever and
meningeal signs following cell transplantation.
93
It was
primarily thought that intracerebral administration was
the best way for exogenous neural stem cells to reach the
brain.
94
Intracerebral administration presented im-
planted cells in the lesion size in comparison with other
delivery routes because several million cells are trans-
planted into the brain and approximately 1/3 of the stem
RIKHTEGAR ET AL.
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5
cells migrate toward the damaged regions as well as to
the intact hemisphere.
95
Some clinical trials have used
this intracerebral route during the delayed phases for the
reason that it is safer and more suitable for clinical
applications.
94
Intracranial administration of stem cells,
mainly for MSCs, the transport of stem cells into the
circulation system, offers a smaller amount invasive
treatment. Though, any trials procedure should consider
precautions to eliminate the creation of embolisms
following the cell implantation.
96
Intravenously admini-
strated cells go over the systemic and pulmonary vascular
systems, and settle noticeably at the injured site of
brain.
97
After intravenous administration cells may stick
together and cause microemboli, comprising lethal
pulmonary emboli. The intravenous route is more
possible, suitable, and justified cell therapy practice
during the acute or initial subacute time window of
stroke.
98
In fact, the most ongoing clinical trials use
intravenous administration. Intra‐arterial delivery, by-
passes the peripheral filtering organs, causing to higher
cell engraftment to the brain, and has the superior
effectiveness compared with intravenous infusion.
98
After intra‐arterial delivery, cells may decrease in
cerebral blood flow related to microstrokes.
99,100
Intra‐
arterial route of delivery is superior to the intravenous
route for the reason that the cells would be directly
delivered to the brain where they could act to decline
infarct size and rise functional recovery.
101
Intranasal
transport has arisen as a new method to transfer
therapeutic mediators to the brain through the BBB.
This technique is noninvasive and eases cell homing to
the CNS and decreases the possible side effects related to
intravascular administration.
102,103
More progressive de-
livery techniques are also being evaluated, comprising
bioengineered polymers to improve stem cell survival and
effectiveness. Inert polymer matrices, such as hydrogels
and particles, were first applied for stem cell delivery.
104
The various delivery routes to transport the cells to the
stroke region have summarized in Table 1.
5
|
CLINICAL TRIALS OF STEM
CELLS TO STROKE
Literature review revealed that numerous clinical trials
are being conducted on therapeutic effects of stem cells
for stroke. Ten clinical trials of intravascular delivery of
the cells, containing 136 subjects, have been described to
date.
51
The immortalized cell line of teratocarcinoma‐
derived Ntera2/D1 neuron‐like cells (NT2N) were the
primary human cells applied in a Phase I clinical trial for
patients with stroke and were transplanted into the
infarcted area of 12 subjects, six months to six years
afterward a basal ganglia stroke.
105
Functional develop-
ment was seen in this small group of patients without any
important adverse events. In a successive Phase II trial,
NT2N cells were transplanted into the peri‐infarct or
peri‐hemorrhagic cavity and again promising results
were seen without any unfavorable events.
106
In an
open‐label, single‐blinded randomized trial, 50 to 60
million autologous MSCs suspended in 250 mL of saline
were infused intravenously between 3 months and 2
years after stroke. This study presented important
TABLE 1 Routes of cell administration for treatment of stroke
Delivery route Features
Intraparenchymal ‐Early neural transplantation studies
‐Safety and feasibility, but not
efficacy Cause to:
‐Motor worsening
‐Syncope
‐Chronic subdural hematoma
Intracerebroventricular ‐For NSC transplantation Cause to:
‐Fever
‐Meningeal signs
Intracerebral ‐Invasiveness
‐Poor cell availability
‐Immune rejection
‐Uncertain fate in the brain
Development in neurological
consequences
Intracranial ‐Mainly for MSCs transplantation
‐Less invasive
Intravenous ‐Modest invasiveness
‐Promote the extensive secretion of
neuroprotective, proangiogenic,
and immunomodulatory factors
‐Reduce infarct size
‐Induce functional (motor and/or
cognitive) recovery
‐Majority of cells become trapped in
the lung, liver, and spleen
‐Cells may stick together and cause
microemboli
Intra‐arterial ‐Higher cell engraftment to the
brain‐modest invasiveness
‐Promote the extensive secretion of
neuroprotective, proangiogenic,
and immunomodulatory factors
‐Decrease in cerebral blood flow
Intranasal ‐Noninvasive method
‐Poor cell engraftment
‐Eases cell homing to the CNS
Intrathecal ‐For UCMSCs transplantation
‐Improve motor function
‐Decrease ischemic damage of
stroke
Abbreviations: MSCs, mesenchymal stem cells; NSC, neural stem cells;
UCMSCs, umbilical cord mesenchymal stem cells.
6
|
RIKHTEGAR ET AL.
improvement in functional consequence according to the
Modified Rankin Scale (mRS) in the treatment group.
107
In this study, the lesion volume was decreased by 20%
and extraordinarily, no tumorigenesis and venous embo-
lism were revealed. The outcome clearly illustrated the
hopeful possible use of MSCs in clinical settings.
107
In a
SanBio‐Phase I study, altered donor human BM‐derived
MSCs (Notch‐transfected mesenchymal stromal cells
(SB623 cells) to enhance cell viability) was used. Eighteen
male or female patients were transplanted with 2.5, 5, or
10 million cells between 6 and 60 months (average 22
months) following ischemic stroke.
108
Neurological
function and motor scales above the first 2 to 3 months
post transplantation displayed modest progresses and
were sustained up to 12 months in 16 of the 18 subjects.
This study described the development of hyperintensities
around the needle tracts on T2‐weighted fluid attenuated
inversion‐recovery (FLAIR) scans in most of the patients.
This phenomena was observed one week after transplan-
tation in the SanBio study. However, higher range of T2
hyperintensity was described to associated with develop-
ment in motor damage at 12 months according to the
Fugl‐Meyer motor scale.
108,109
After the hopeful results of
SanBio's early‐phase trial implementing SB623 cells in
chronic stroke, a phase IIb study of a double‐blind, sham
surgery randomized controlled trial, ACTISSIMA (Allo-
geneic Cell Therapy for Ischemic Stroke to Improve
Motor Abilities) has been registered to examine the
effects of stereotactic intracranial implantation of SB623
cells in patients with fixed motor deficits caused by
ischemic stroke.
110
In this study 156 patients from 65
sites in the United States will be enrolled and randomize
patients will be divided into two groups. First group of
patients will receive 2.5 million or 5.0 million SB623 cells,
whereas, the second group subjects will get administrated
by sham placebo injections. The proposed time frame for
this study has been set for 1 year with the primary end
point at 6 months. Patients will be followed for an
additional 6 months. The proportion of patients whose
Fugl‐Meyer motor function total score advances by ≥10
points at month 6 compared with the control group will
illustrate the effectiveness of the treatment of ACTISSI-
MA study.
110
In the ISIS‐HERMES trial, autologous
MSCs injected intravenously in 31 subacute stroke
patients. This study has also been finalized, nevertheless,
the date is not yet accessible.
111
In a randomized
controlled double‐blinded phase Ⅰ/Ⅱclinical trial study,
intravenous administration of autologous BM‐derived
MSC in patients with chronic stroke was performed and
the recovery from hemorrhage were confirmed after the
one year of MSC treatment.
112
Now, accessible data on
clinical trials of MSC therapy indicate that this treatment
improves neurorestoration by rise of neural plasticity and
reduction of lesion volume.
113,114
In a large multicenter
academically funded European trial, Regenerative Stem
Cell Therapy for Stroke in Europe (RESSTORE), adipose‐
derived donor MSCs transported intravenously 14 days
after ischemic stroke for a group of 400 patients.
109
The
data from this study, however, has not yet published. In
another clinical trial on stem cell therapy for acute
stroke, bone marrow mononuclear cells (BMMNCs)
improved the clinical consequences through a decrease
in the National Institute of Health Stroke Scale (NIHSS)
score six months after transplantation.
115
Clinical trials
using BMMNCs have revealed its safety and practicability
in the acute and chronic phases of recovery.
116
A phase 1/
2A study, which implemented human altered bone
marrow–derived stromal cells, presented safety and
feasibility of direct intracerebral implantation six months
to five years after stroke, and also progress in neurolo-
gical consequences.
117
In another clinical trial, the
intrathecally transferred autologous BMMNCs in patients
with chronic stroke, developed the prognosis of practical
recuperation.
118
Intravenous autologous BMMNCs trans-
plantation enhanced the cerebral blood flow and led to
neurological improvement.
119
A Phase 2 randomized,
controlled trials with blinded end‐point valuation took
place at five centers in India. In this study, autologous
BMMNCs transported intravenously at average of 18 days
afterward stroke onset.
120
Sixty patients were assigned to
control and 60 patients to cell‐therapy injection groups.
Approximately 281 million cells were infused, of which
about 1% was CD34
+
cells. No alterations in functional
consequences were observed through 6 months after
follow‐up.
120
In a recent clinical trial, the safety and
effectiveness of 3 × 10
6
or more autologous BMMNC
transfer in patients with stroke were administrated and
improved consequence in patients with stroke were
accounted.
121
The MASTERS trial was a randomized
double blind dose escalation trial evaluating allogeneic,
adult‐derived stem cells (MultiStem, Athersys) in the
treatment of early cortical strokes.
122
In randomized
Athersys MultiStem study, intravenous infusion of
allogeneic multipotent adult progenitor cells (MAPCs),
(multipotent bone marrow derivative cells defunct of
CD45
+
/glycophorin‐A
+
cells) were administrated,
48 hours after onset of ischemic stroke and patients were
then followed for 6 months.
123,124
In this trial, 126
participants (65 and 61 for MAPCs therapy and placebos
respectively) were involved. The MAPCs group showed a
tendency to improved functional consequences within
36 hours post treatment.
125
MultiStem reduces immune
activation and inflammatory responses whereas increases
neurogenesis and differentiation. Decrease in spleen size
that happens subsequent stroke is prohibited
through MultiStem administration along with immune
RIKHTEGAR ET AL.
|
7
TABLE 2 Major clinical trials investigated stem cells therapies for stroke treatment
Cell type Cell source Patient characteristics
Cell volume and
administration time Outcome Adverse effects Reference
1 LBS neurons
(Layton Bioscience
Phase I)
‐Immortalized cell lines
Ntera2/D1 Neuron‐Like
Cells (NT2N)
‐12 Ischemic stroke patients
(6 m–6 y after stroke)*
‐2 Million cells, 6 million
cells
‐Feasible ‐Kondziolka
et al
105
‐Age: 44–75 y ‐Intracerebral ‐Improve function
2 LBS neurons
(Layton Bioscience
Phase II)
‐Immortalized cell lines
Ntera2/D1 Neuron‐Like
Cells (NT2N)
‐14 Stroke patients (1–6 y after
stroke)
‐5 Million cells, 10 million
cells
Improve in: ‐ARAT ‐Seizure Kondziolka
et al
106
‐Age: 18–75 y ‐Intracerebral ‐Cognitive outcome ‐Syncope
‐Neurological
function
‐Subdural hematoma
3 SB623 cells (SanBio–
Phase I)
‐Notch‐transfected
mesenchymal stromal
cells
‐18 Stroke patients (6‐60 m after
stroke)
‐2.5 Million cells, 5 million
cells, 10 million cells
Improve in: ‐Steinberg
et al
108
‐Age: 18–75 y ‐Intracerebral ‐Fugl‐Meyer score
‐NIHSS > 7 ‐NIHSS
4 SB623 cells (SanBio–
Phase II;
ACTISSIMA)
‐Notch‐transfected
mesenchymal stromal
cells
‐156 patients group 1 (2.5 million
or 5.0 million cells), group 2
(sham placebo); ( > 6‐<60m
after stroke)
‐2.5 Million cells, 5 million
cells
Improve in: ‐Wechsler
et al
110
‐Intracerebral ‐Fugl‐Meyer motor
function total score
‐ARAT
5 Autologous (ISIS‐
HERMES trial)
‐MSCs ‐31 subacute stroke patients and 11
controls
‐Intravenous ‐Unpublished Data ‐Detante et al
111
6‐Allogeneic
(Athersys
MultiStem study)
‐MAPCs ‐126 Stroke patients; (48 h) ‐Intravenous Improve in ‐Restricted
employment in
patients with motor
deficits
Hess et al
123,124
‐Fugl‐Meyer motor
scale
7 CTX0E03 cells
(ReNeuron‐
PISCES I)
‐c‐mycER transgene
human fetal neural stem
cells
‐Unilateral ischemic stroke
comprising subcortical white
matter or basal ganglia (6 m–5y)
‐2 Million cells, 5 million
cells, 10 million cells, 20
million cells
Improve in: Muir
109
‐Age: 60–85 y ‐Intracerebral ‐NIHSS
‐NIHSS _6 ‐Ashworth spasticity
Scale
‐Modest T2 FLAIR
(Continues)
8
|
RIKHTEGAR ET AL.
suppression as a significant mechanism of act of these
cells.
122
After MultiStem administration, there was a
substantial decrease in circulation CD3
+
T cells at
48 hours along with major declines in IL‐1β,IL‐6, tumor
necrosis factor (TNF‐α), and IFN‐λat 7 days that were
normalized at 30 days.
126
In another recent clinical trial,
developed neurological function was revealed subsequent
implantation of an preserved human neural stem‐cell line
with no adverse events.
127
Now, ReNeuron, a British
founded company, is sponsoring a Phase I clinical trial,
exploring the clinical use of a CTX0E03; human fetal
neural stem cells genetically altered by insertion of a c‐
mycER transgene that expresses the c‐myc growth factor
when stimulated by 4‐hydroxytamoxifen, for stroke
treatment.
128
During a Pilot Investigation of Stem Cells
for Stroke (PISCES 1) trial one dose of 2 to 20 million
cells transplanted through stereotaxic intraputaminal
injection to the ipsilesional hemisphere of patients at 6
to 60 months following ischemic stroke and followed for
2 years after treatment.
128,129
In this study, 11 male
patients experienced transplantation with average of 22
months after stroke. Modest developments in motor
function happened in the primary 2 months afterward
transplantation and were sustained subsequently.
109
PISCES 1 informed more milder T2 FLAIR hyperinten-
sities one month after transplantation which was
continued for 12 months.
130
In the PISCES 2 study, 21
male and female patients, 2 to 12 months after stroke
onset, were treated with 20 million CTX0E03 cells
stereotactically through implantation into the putamen.
At 1 year, no safety concerns related to the cells were
reported, and seven patients improved their MRS score
by at least 1 grade. Overall, 15 patients showed
improvement on one or more of the clinical scales.
110
Another double‐blind randomized placebo‐controlled
Phase III clinical trial in now in progress which is
investigating the effect of intravenously infusion of
autologous BM‐derived NSC for patients with stroke
from cerebral infarction.
131
In another study, intracranial
administration of autologous human adult dental pulp
stem cell (DPSC) in patients with chronic stroke was
investigated. The main results were confirmed the safety
and practicability of the treatment; in addition, the
maximum acceptable cell number in humans were
defined.
132
In a new meta‐analysis illustrated that stem
cell therapy could considerably improve neurological
functions and quality of life, however, further clinical
trials are required to confirm the clinical use of stem cell
implantation.
133,134
While the most recent clinical trials
using allogeneic cells (SB623, MultiStem, and CTX0E03)
did not need immunosuppression, the potential for
allergic reaction remains. Autologous cells have need of
bone marrow harvest, causing to variable stem cell yield
TABLE 2 (Continued)
Cell type Cell source Patient characteristics
Cell volume and
administration time Outcome Adverse effects Reference
8 CTX0E03 cells
(ReNeuron‐
PISCES II)
‐c‐myc ER transgene
human fetal neural stem
cells
‐21 stroke patients; (2‐12 m) ‐20 Million cells Improve in: Wechsler
et al
110
‐Intracerebral ‐ARAT
‐mRS
‐Fugl‐Meyer
Abbreviations: ARAT, action research arm test; CTX0E03, c‐mycER transgene human fetal neural stem cells; FLAIR, fluid attenuated inversion recovery; LBS, Layton Bioscience; MAPCs, multipotent adult progenitor
cells; mRS, Modified Rankin Scale (a functional outcome scale with 0‐3 being capable to walk with variable degrees of disability); NIHSS, National Institutes of Health Stroke Scale; NT2N, teratocarcinoma‐derived
Ntera2/D1 neuron‐like cells.
*
(6 m–6 y): 6 mo and 6 y after stroke.
RIKHTEGAR ET AL.
|
9
and need time for expansion previous to administration,
nonetheless carry fewer concern for allergic reaction or
rejection.
135
Beside the possible positive consequence of
stem cell therapy, numerous queries have raised on its
clinical applications. Up to date, cell therapies has not yet
reported to be problematical. Affirmation of effectiveness
in randomized, double‐blinded trials are required, how-
ever, many clinical trials are in progress to assess whether
cell‐based therapy would develop the subsequent mod-
ality of recovery for stroke consequences. Major clinical
trials investigated stem cells therapies for stroke treat-
ment are summarized in Table 2.
6
|
FUTURE PERSPECTIVES AND
CONCLUSION
Stroke remains the most common reason of death in the
mainstream of developed countries, thus requires serious
attention through conducting preclinical studies at both
acute and chronic stages. Ischemic stroke, prompts acute
neuroinflammation that can aggravate the initial brain
injury.
136
Regenerative medicine in stroke consists of
therapies that could prompt tissue repair leading to
recovery. Numerous alternate attitudes comprising the
usage of ESCs, MSCs, NSC, and iPSCs have been attempted
to treat severe neuronal and functional damages occur
generally after a stroke. Most current clinical trials target to
measure the safety and feasibility of administration routs of
different human adult stem cells in patients with stroke and
aim to define the maximum allowable doses. However,
FDA has not yet accepted any cell‐based treatment of acute
and chronic stroke. In summary, cell transplantation for
stroke treatment in humans is still in its infancy. There is a
necessity for more basic and translational studies to
scientifically demonstrate effectiveness of cell therapies in
clinical settings. We anticipate that extra efforts on stem cell
therapy progress, containing clinical trials, will be available
in the immediate prospect.
ACKNOWLEDGMENTS
The authors would like to thank the Aging Research
Institute, Tabriz University of Medical Sciences for
supporting this study.
CONFLICTS OF INTEREST
The authors report no conflicts of interest in this study.
ORCID
Mehdi Yousefi http://orcid.org/0000-0003-0099-6728
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How to cite this article: Rikhtegar R, Yousefi M,
Dolati S, et al. Stem cell‐based cell therapy for
neuroprotection in stroke: A review. J Cell Biochem.
2018;1‐14. https://doi.org/10.1002/jcb.28207
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