Experimental Neurology 369 (2023) 114543

Contents lists available at ScienceDirect

Experimental Neurology
journal homepage: www.elsevier.com/locate/yexnr

Review Article

Stem cells in central nervous system diseases: Promising

therapeutic strategies
Caidi Ying a, b, 1, Jiahao Zhang a, b, 1, Haocheng Zhang a, b, 1, Shiqi Gao a, b, Xiaoming Guo a, b,
Jun Lin a, b, Haijian Wu a, b, *, Yuan Hong a, b, *
a
Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
b
Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, China

A R T I C L E I N F O A B S T R A C T

Keywords: Central nervous system (CNS) diseases are a leading cause of death and disability. Due to CNS neurons have no
Stem cell self-renewal and regenerative ability as they mature, their loss after injury or disease is irreversible and often
Cell therapy leads to functional impairments. Unfortunately, therapeutic options for CNS diseases are still limited, and
Central nervous system diseases
effective treatments for these notorious diseases are warranted to be explored. At present, stem cell therapy has
Immunoregulation
Neurotrophic effect
emerged as a potential therapeutic strategy for improving the prognosis of CNS diseases. Accumulating pre­
Cell replacement clinical and clinical evidences have demonstrated that multiple molecular mechanisms, such as cell replacement,
immunoregulation and neurotrophic effect, underlie the use of stem cell therapy for CNS diseases. However,
several issues have yet to be addressed to support its clinical application. Thus, this review article aims to
summarize the role and underlying mechanisms of stem cell therapy in treating CNS diseases. And it is worthy of
further evaluation for the potential therapeutic applications of stem cell treatment in CNS disease.

1. Introduction
CNS diseases are among the most prevalent disorders affecting the
nervous system, leading to irreversible damage and loss of functionality
(Menorca et al., 2013; Walshe, 2014). These diseases are associated with
high mortality and disability rates, imposing a significant burden on
society(Feigin et al., 2021). Traditionally, it was believed that the neu­
rons in the CNS of adult mammals lacked the ability to regenerate
spontaneously following injury(Huebner and Strittmatter, 2009).
Furthermore, the therapeutic options for CNS diseases are often
impeded by the complex and incompletely understood mechanisms
underlying their pathogenesis(Sakowski and Chen, 2022). Neurode­
generative diseases, in particular, involve intricate interactions among
multiple cell types and metabolic processes within a complex microen­
vironment(Dugger and Dickson, 2017). Similarly, CNS injuries such as
stroke, spinal cord injury (SCI), and traumatic brain injury (TBI) trigger
a cascade of detrimental events that profoundly impact neurological
health(Uyeda and Muramatsu, 2020). Consequently, there is a pressing
need for therapeutic strategies that can facilitate the restoration of
neurological function in the CNS.
Stem cell therapy has garnered considerable attention as a prospec­
tive treatment modality for CNS diseases. The utilized stem cells
encompass embryonic stem cells (ESCs), induced pluripotent stem cells
(iPSCs), neural stem cells (NSCs), mesenchymal stem cells (MSCs), and
other stem cell variants(Liau et al., 2020; Zhou et al., 2021; Huang et al.,
2021). Extensive research has focused on investigating the application
of stem cell therapy in numerous neurodegenerative diseases and CNS
injuries, with relatively limited exploration in the context of tumors and
infections(Huo et al., 2014; Gao et al., 2020). Extensive investigations
have delved into the potential mechanisms underlying the protective

Abbreviations: CNS, central nervous system; SCI, spinal cord injury; TBI, traumatic brain injury; ESCs, embryonic stem cells; iPSCs, induced pluripotent stem cells;
NSCs, neural stem cells; MSCs, mesenchymal stem cells; PD, Parkinson’s disease; ALS, amyotrophic lateral sclerosis; SVZ, subventricular zone; AD, Alzheimer’s
disease; BM-MSCs, bone marrow-derived mesenchymal stem cells; MUSE cells, Multilineage-Differentiating Stress-Enduring Cells; DA, dopamine; Aβ, amyloid-β;
AChEI, acetylcholinesterase inhibitors; UMN, upper motor neurons; LMN, lower motor neurons; MNs, motor neurons; AMSCs, amnion-derived mesenchymal stem
cells; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; NT-3, neurotrophin-3; ROS, reactive
oxygen species; iNPCs, induced neural progenitor cells.
* Corresponding authors at: Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
E-mail addresses: haijwu@zju.edu.cn (H. Wu), hy0904@zju.edu.cn (Y. Hong).
1
Drs. Caidi Ying, Jiahao Zhang and Haocheng Zhang contributed equally.

https://doi.org/10.1016/j.expneurol.2023.114543
Received 9 July 2023; Received in revised form 11 September 2023; Accepted 14 September 2023
Available online 22 September 2023
0014-4886/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
C. Ying et al.
role of stem cells, including their secretory function, anti-inflammatory
properties, and capacity for cellular replacement(Xian et al., 2019; De
Gioia et al., 2020; Ford et al., 2020).
This review examines the pathological characteristics of CNS dis­
eases as potential targets for stem cell therapy. The types of stem cells
currently used in stem cell therapy and their neuroprotective mecha­
nisms are also discussed. The review analyzes the limited achievements
and future development trends of stem cell therapy, addressing the ex­
pectations and concerns of clinical application.
2. Stem cell therapies for central nervous system diseases
2.1. Types of stem cells
2.1.1. Embryonic stem cells
ESCs, derived from the inner cell mass of developing embryos, have
the potential to differentiate into various cell types(Martínez-Morales
et al., 2013). Their transplantation in stem cell therapy is utilized for
CNS diseases such as Parkinson’s disease (PD) and SCI(Freed et al.,
2001; Shao et al., 2019). The differentiation of ESCs into neural pre­
cursor somatic cells, neural lineage cells, NSCs, and other secondary
cells can be induced through interactions with bone marrow stromal
cells, small molecule inhibitors, or other methods(Drury-Stewart et al.,
2013). Ethical concerns, tumorigenicity, immune rejection, and other
related issues surrounding the application of ESCs have been widely
discussed, limiting their use(Ratajczak et al., 2019).
2.1.2. Induced pluripotent stem cells
iPSCs are generated by reprogramming adult cells into an embryoid
state, allowing them to differentiate into various cell types(Shahbazi
et al., 2018). iPSCs share similar advantages with ESCs as they possess
pluripotency and self-renewal capabilities(Takahashi and Yamanaka,
2006; Phanstiel et al., 2011). In comparison to ESCs, iPSCs offer benefits
such as ease of acquisition, ease of cultivation, and reduced immuno­
genicity(Vitrac and Cloëz-Tayarani, 2018). iPSCs find application in
stem cell therapy for CNS diseases like amyotrophic lateral sclerosis
(ALS) and SCI(Kim et al., 2014; Shao et al., 2019). However, it is
important to note that while iPSC differentiation into neurons or glial
cells may enhance the efficacy of stem cell therapy, there is a potential
risk of tumorigenicity(Suda et al., 2020).
2.1.3. Neural stem cells
NSCs possess the capability to differentiate into neurons, astrocytes,
and oligodendrocytes(Urbán et al., 2019). In adult mammals, NSCs are
predominantly found in specific regions, notably the subventricular
zone (SVZ) and the dentate gyrus of the hippocampus(Grochowski et al.,
2018). The behavior of NSCs is regulated by various factors, determining
whether they remain quiescent or enter an active state(Lugert et al.,
2010). In the adult human hippocampus, approximately 700 new neu­
rons are generated each day, albeit with a moderate decline associated
with aging(Spalding et al., 2013). These newly formed neurons
contribute significantly to the plasticity of the nervous system(Toda and
Gage, 2018). The continuous depletion of the neural stem cell (NSC)
pool within the hippocampus is considered the primary cause of age-
related decline in neurogenesis(Encinas and Sierra, 2012). Both exoge­
nous NSC transplantation and endogenous NSC regulation have been
extensively investigated in numerous CNS diseases, including Alz­
heimer’s disease (AD) and stroke(Lilja et al., 2015; Huang and Zhang,
2019). Given the robust differentiating capacity of NSCs into neuronal
cells, transplantation of NSCs has demonstrated effective promotion of
neural function recovery in preclinical studies(Huang et al., 2021).
2.1.4. Mesenchymal stem cells
MSCs possess the ability for self-renewal and multi-directional dif­
ferentiation into various cell types, and they can be derived from nearly
any type of tissue(Ding et al., 2011). Among them, bone marrow-derived
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Experimental Neurology 369 (2023) 114543
mesenchymal stem cells (BM-MSCs) have been extensively investigated
and demonstrated their capacity to differentiate into neurons or glial
cells, facilitating the replacement of damaged cells in brain tissue
(Alexanian et al., 2008; Yan et al., 2013). Additionally, MSCs exert a
neuroprotective function through the secretion of neurotrophic growth
factors and other mechanisms(Wakabayashi et al., 2010). The mecha­
nisms underlying the therapeutic effects of MSCs have been widely
explored in neurological disorders, such as TBI and SCI(Wang et al.,
2017; Shao et al., 2019).
2.1.5. Meninges-derived stem cells
Meninges-derived stem cells, a specialized category of stem cells
originating from the meninges, exhibit remarkable capabilities in
generating diverse neural cell types, encompassing neurons and glial
cells(Bifari et al., 2017; Đặng et al., 2019). Their innate regenerative
potential implies a pivotal role in restoring and rejuvenating impaired or
degenerated neural tissues within the central nervous system, holding
significant promise for advancing innovative therapeutic approaches
addressing a range of neurological disorders, including stroke and SCI.
(Decimo et al., 2011; Nakagomi et al., 2012). These stem cells constitute
an intriguing and relatively unexplored realm of research, representing
previously overlooked sources of in vivo nerve regeneration, and they
may exert a profound influence on the evolution of stem cell-based
therapies for neurological diseases.
2.1.6. Other types of stem cells
There are some other types of stem cells, such as Multilineage-
Differentiating Stress-Enduring Cells (MUSE cells), Dental Pulp Stem
Cells, Hematopoietic Stem Cells (CD34 Positive), Endothelial Progenitor
Cells and Neural Crest Stem Cells (NCSCs), that have also been used to
study the mechanisms of nerve regeneration in models such as stroke
and SCI(Hennemann et al., 2008; Sakai et al., 2012; Park et al., 2014;
Müller et al., 2015; Uchida et al., 2016). At present, there are few studies
on these stem cells in CNS diseases, and they will not be introduced in
detail in this review.
2.2. Stem cell therapies for neurodegenerative diseases
Stem cell therapy has emerged as a valuable approach in the treat­
ment of various CNS diseases, particularly neurodegenerative diseases.
Neurodegenerative diseases are characterized by the progressive
degeneration and loss of neurons in terms of structure, function, or
quantity(Yuan and Yankner, 2000). PD, AD, and ALS are the three main
neurodegenerative diseases(Checkoway et al., 2011). The current drug
treatments and surgical interventions for neurodegenerative diseases are
unable to effectively halt the degenerative processes(Sudhakar and
Richardson, 2019). Nowadays, stem cell therapy offers promising stra­
tegies for addressing a wide range of neurodegenerative diseases(Sak­
thiswary and Raymond, 2012).
2.2.1. Parkinson’s disease
PD is a prevalent progressive neurodegenerative disorder charac­
terized by a deficiency of dopamine (DA) in the striatum, primarily due
to the loss of DA-producing neurons located in the substantia nigra
(Buddhala et al., 2015). The current primary treatment approach for PD
involves the administration of levodopa, a precursor of DA, to
compensate for the DA deficiency resulting from the destruction of
dopaminergic neurons(Jankovic and Tan, 2020). While drug treatment
can alleviate symptoms, it does not halt or reverse the progression of
neurodegeneration(Reich and Savitt, 2019).
The transplantation of human embryonic dopaminergic neurons into
the striatum of PD patients holds promise as a potential treatment(Freed
et al., 2001). Transplanted stem cells have demonstrated survival in
patients with severe PD, successfully differentiating into functional DA
neurons and continuing DA production(Piccini et al., 1999). However,
the clinical effectiveness of stem cell transplantation remains variable,
C. Ying et al.
possibly due to differences among transplanted cells(Olanow et al.,
2003). Despite existing challenges in generating the appropriate type of
DA neurons and improving conditions to enhance the survival of
transplanted cells, there is optimism regarding the potential of stem cells
to induce the generation of functional DA neurons and serve as a form of
cell therapy(Kim, 2011).
2.2.2. Alzheimer’s disease
AD is the most prevalent cause of dementia(Terry and Davies, 1980).
The primary pathological mechanism of AD involves the accumulation
of amyloid-β (Aβ) protein, leading to the degeneration and loss of neu­
rons and synapses in various regions of the brain(Moreno-Jiménez et al.,
2019; Huang et al., 2021). The cholinergic system plays a crucial role in
the regulation of learning and memory. Hence, the use of acetylcho­
linesterase inhibitors (AChEI) can partially alleviate cognitive impair­
ment in AD(Musiał et al., 2007). However, as drug therapy for AD is
primarily palliative and does not slow down or reverse the progression
of the disease, effective treatment options are needed to address the
needs of AD patients(Park et al., 2020). Stem cell therapy for AD holds
promise in meeting this requirement.
Transplantation of NSCs has shown promise in enhancing endoge­
nous neurogenesis and preventing further cognitive decline, as evi­
denced by animal experiments(Lilja et al., 2015). However, the
therapeutic potential of NSCs can be hindered by pathological high
levels of oxidative stress, which can damage neurons and impair
neurogenic effects(Huang et al., 2021). Current strategies primarily
focus on directing the differentiation of NSCs into neurons and opti­
mizing the microenvironmental components to enhance neurogenesis
(Yu et al., 2020). Integration of NSC transplantation with gene editing,
nanomaterials, drug interventions, and other approaches has been
explored to improve the efficacy of stem cell therapy(Choi et al., 2018;
Bhattarai et al., 2020; Yu et al., 2020). Nonetheless, transitioning from
animal experiments to clinical applications still requires significant ef­
forts and research endeavors.
2.2.3. Amyotrophic lateral sclerosis
ALS is a fatal neurodegenerative disease in adults(Hulisz, 2018). ALS
simultaneously accumulate upper motor neurons (UMN) and lower
motor neurons (LMN), which manifested as a progressive paralysis
(Ustyantseva et al., 2020). The disease typically progresses rapidly, with
respiratory failure and death occurring within one to five years after
symptom onset(Yang et al., 2021). While the exact pathogenesis of ALS
remains unclear, neuronal dysfunction is believed to be caused by ge­
netic mutations and abnormal protein deposition(Oskarsson et al.,
2018). Among the various drugs tried for ALS patients, riluzole is
currently the only approved medication that directly modifies the course
of the disease(Dharmadasa and Kiernan, 2018). Numerous therapies,
including anti-apoptotic drugs, anti-oxidant drugs, anti-aggregation
drugs, and anti-excitotoxicity drugs, are being investigated at various
stages of preclinical and clinical evaluation(Nowicka et al., 2019).
However, single-drug treatments have not been able to reverse the loss
of motor neurons (MNs) seen in ALS(Ralli et al., 2019).
With the expanding research on stem cells, particularly iPSCs, stem
cell therapy has emerged as a promising approach for MNs regeneration
(Kim et al., 2014). In comparison to MSCs, NSCs derived from the spinal
cord not only release beneficial growth factors but also integrate into the
neural circuitry of the MNs and spinal cord, forming appropriate syn­
apses(Lunn et al., 2014). Although the safety of stem cell transplantation
in ALS patients has been demonstrated, there are still several challenges
that need to be addressed in this treatment approach, including the
handling of stem cells and monitoring clinical outcomes(Giacomelli
et al., 2022).
In addition to the mentioned neurodegenerative diseases, there are
various types of neurodegenerative diseases. The fundamental mecha­
nism underlying most neurodegenerative diseases involves the pro­
gressive loss of neuronal structure, function, or number, often
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Experimental Neurology 369 (2023) 114543
accompanied by neuronal death(Sakthiswary and Raymond, 2012).
Stem cells possess the ability to repair damaged neuronal tissue, replace
damaged or lost cells with differentiated neuronal cells, create a favor­
able environment for neural regeneration, or provide protection to
existing healthy neurons and glial cells against further damage
(Sivandzade and Cucullo, 2021). While there are currently numerous
clinical trials focused on stem cell therapy for neurodegenerative dis­
eases, it is important to acknowledge that several challenges and ob­
stacles must be addressed before the widespread clinical utilization of
stem cells(Bednar and Perry, 2012).
2.3. Stem cell therapies for central nervous system injury
Stem cell therapy is not only applied to neurodegenerative diseases,
but also applied to CNS injury, such as TBI, SCI and stroke(Nout-Lomas,
2022). While the microenvironment of the nervous system in the acute
stage of injury may not be conducive to the survival and differentiation
of NSCs, studies have shown that transplantation of stem cells at specific
time points can be feasible(Ogawa et al., 2002). Stem cell trans­
plantation holds promise as an appealing approach to restore nerve
function in individuals following nerve injuries(Wang et al., 2017).
2.3.1. Traumatic brain injury
TBI is a prevalent condition in neurosurgery characterized by a high
mortality and disability rate. Despite numerous therapeutic approaches
attempted for TBI, many patients with head injuries continue to expe­
rience significant brain damage and behavioral disorders(Wang et al.,
2012). Currently, there is no clinical treatment available that can reverse
the pathological cascade of cell death and effectively enhance neuro­
behavioral outcomes(Longhi et al., 2005). Promising strategies
involving drug-based or cell-based therapies, such as erythropoietin,
statins, bone marrow stromal cells, and stem cells, have been explored to
promote brain remodeling through processes like angiogenesis, neuro­
genesis, and synaptogenesis, which aim to improve the functional out­
comes for individuals with TBI(Xiong et al., 2009). In recent years, NSC
therapy has garnered significant attention in the field.
MSCs have demonstrated potential in the treatment of TBI due to
their ability to promote neural regeneration and exert neurotrophic ef­
fects(Wang et al., 2017). Human amnion-derived mesenchymal stem
cells (AMSCs) and BM-MSCs are promising sources of MSCs that have
shown the ability to enhance the expression of neurotrophic factors,
thereby facilitating nerve regeneration(Guan et al., 2013; Anbari et al.,
2014). However, stem cell therapy still faces several challenges,
including the low survival rate of transplanted stem cells and their
limited differentiation capacity(Bae et al., 2021). Combining stem cell
therapy with biomaterials holds promise for addressing these challenges
by improving the survival rate of stem cells, creating a conducive
environment for their survival, and supporting the regeneration of TBI
(Liu et al., 2022).
2.3.2. Spinal cord injury
SCI is a severe condition characterized by the abrupt loss of sensory,
motor, and autonomic functions below the level of the injury(Mothe and
Tator, 2012). Despite extensive efforts and resources invested, no
treatment has been able to achieve substantial improvement or signifi­
cant functional recovery of the injured nerves(Tator, 2006). Current
treatment approaches primarily focus on reducing secondary compli­
cations and maximizing residual function through rehabilitation efforts
(Dell’Anno and Strittmatter, 2017). The differentiation of NSCs within
the spinal cord holds promise as a potential strategy to replenish the lost
neurons following SCI(Zhao et al., 2017a).
Several types of NSCs, including MSCs derived from various tissue
sources, ESCs, and iPSCs, have been investigated for their potential in
treating SCI(Shao et al., 2019). Endogenous NSCs within the spinal cord
are also considered as therapeutic targets for SCI, although their func­
tion requires external regulation(Gilbert et al., 2022). When NSC grafts
C. Ying et al.
are transplanted into the site of SCI, they can integrate and form func­
tional synaptic subnetworks, which can be beneficial for the recovery of
nerve function(Ceto et al., 2020). Furthermore, NSC-derived exosomes
and small extracellular vesicles have been identified as important me­
diators in promoting nerve regeneration(Zhong et al., 2020). Enhancing
the delivery of NSCs can be achieved through approaches such as stent
placement or combined immunotherapy, which have shown potential in
improving the treatment efficacy for SCI(Liau et al., 2020; Chen et al.,
2022).
2.3.3. Stroke
Stroke, particularly ischemic stroke, is a leading cause of mortality
and disability globally, with ischemic stroke accounting for over 80% of
all stroke cases(Benjamin et al., 2017). While reperfusion therapy is
currently the main effective treatment, its administration is time-
sensitive, and only a limited number of patients can benefit from it
(Hankey, 2017). Stroke-related disabilities often lead to long-term im­
pairments, and conventional rehabilitation approaches often yield
limited results, imposing significant social and economic burdens(Jiao
et al., 2021). Stem cell transplantation holds great promise as a potential
treatment for stroke, and extensive research has been conducted in this
area(Huo et al., 2014; Zhao et al., 2022).
Stem cell therapy is expected to reconstruct the neural network
which was injured by stroke(Kalluri and Dempsey, 2008). NSC trans­
plantation has been proved to promote functional recovery after brain
injury through a variety of by stander mechanisms, rather than simple
cell replacement(Huang and Zhang, 2019). NSCs exhibit anti-
inflammatory properties in stroke treatment, exerting their effects
through mechanisms such as anti-apoptosis, angiogenesis, production of
growth factors, neuroprotection, and anti-fibrosis(Trounson and
McDonald, 2015). Furthermore, intra-venous and intra-arterial admin­
istration of BM-MSCs and MSCs have also shown effectiveness in stroke
treatment, mediated by neuroprotective mechanisms(Chrostek et al.,
2019). Therefore, further research exploring the role and mechanisms of
stem cells in nerve regeneration following stroke holds significant
importance for future clinical applications.
In addition, stem cell therapy is also used for peripheral nerve injury,
ischemic hypoxic encephalopathy, and other nerve injury diseases,
which plays a role in nerve regeneration and anti-inflammatory, and
improve nerve damage(Shi et al., 2009; Feng et al., 2013; Donega et al.,
2014; Lee et al., 2016; Saeki et al., 2022). Further research and clinical
trials are still needed if stem cell therapy is to be used in clinical
treatment.
3. Molecular mechanisms underlying stem cell therapies for
central nervous system diseases
In recent years, significant progress has been made in understanding
the pathophysiological mechanisms of various neurological diseases,
which has identified numerous potential targets for stem cell therapy. In
this part, we will review the molecular mechanism of stem cell therapies
for CNS diseases from both preclinical evidence and clinical findings.
3.1. Preclinical evidence of stem cell therapies for central nervous system
diseases
Preclinical research has provided valuable insights into the molec­
ular mechanisms underlying stem cell-based neural regeneration ther­
apy. Stem cells have been found to secrete growth factors and cytokines
that facilitate neural survival, axon regeneration, and neurogenesis,
contributing to the recovery of neural function(De Gioia et al., 2020).
Moreover, stem cells exhibit immunomodulatory properties, reducing
inflammation and modulating the immune response, which can have a
positive impact on neural regeneration(Xian et al., 2019). Additionally,
the integration of stem cells into neural tissue and their ability to form
functional connections with host neurons play a crucial role in
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Experimental Neurology 369 (2023) 114543
promoting neural regeneration(Ford et al., 2020).
3.1.1. Neurotrophic effects
Stem cell therapy offers neuroprotection through the secretion of
various growth factors, such as nerve growth factor (NGF), brain-
derived neurotrophic factor (BDNF), glial cell line-derived neuro­
trophic factor (GDNF) and neurotrophin-3 (NT-3) (Blesch et al., 2002;
Oliveira et al., 2013). The ability of stem cells to provide sustained
release of these growth factors is a significant advantage compared to
direct injection, as growth factors administered directly can be rapidly
diluted and have short half-lives(Ritfeld et al., 2011). Furthermore,
these growth factors not only enhance the neuroprotective effects of
stem cell therapy but also promote the proliferation and differentiation
of stem cells, thereby reinforcing the overall nerve regeneration poten­
tial(Jin-qiao et al., 2009) (Fig. 1).
NGF promotes the proliferation of stem cells and inhibit their dif­
ferentiation into neurons by activating the phosphorylation of Erk1/2
(Wang et al., 2009). However, some studies have shown that NGF pro­
motes the differentiation of stem cells into mature neural phenotype,
which may be determined by the concentration of NGF(Levenberg et al.,
2005).
Multiple studies have demonstrated that the combination of stem
cells and BDNF promotes axonal extension(Bhattarai et al., 2020; Li
et al., 2023). The protective effect of BDNF on apoptosis induction in
stem cells is thought to be mediated through the PI3K/Akt and MAPK
signaling pathways via Trk receptors(Nguyen et al., 2009).
GDNF has demonstrated neuroprotective effects in animal models of
various CNS diseases(Shi et al., 2009; Dulz et al., 2020). The concurrent
administration of GDNF during the early stage of stem cell trans­
plantation improves the stem cell microenvironment, enhances stem cell
survival, and enhances therapeutic efficacy(Zhao et al., 2017b). The
specific mechanisms underlying GDNF-induced neurogenesis and neu­
roprotection have not been fully elucidated, but they are believed to
involve the PI3K/Akt and MAPK signaling pathways(Nicole et al.,
2001).
NT-3 shares structural and functional similarities with NGF and
BDNF, and it also plays a role in promoting nerve repair in stem cells(Wu
et al., 2018; Sun et al., 2020; Li et al., 2021). The impact of NT-3 on cell
proliferation is dose-dependent, with low doses promoting proliferation
and high doses reducing proliferation and inducing stem cell differen­
tiation(Hapner et al., 2006).
The influence of neurotrophic factors on stem cells contributes to the
reinforcement of NSC therapy. Enhancing the expression of neuro­
trophic factors in stem cells or combining them with biomaterials that
release neurotrophic factors at appropriate doses can be advantageous
(Li et al., 2021).
3.1.2. Immunoregulatory effect
In CNS diseases, particularly acute injury conditions, inflammatory
reactions play a significant role in the regeneration of the nervous sys­
tem(Gaudet and Fonken, 2018; Ghaddar et al., 2021; Huang et al.,
2022). Thus, reducing the detrimental effects of inflammatory factors
and creating a microenvironment that promotes neuronal regeneration
is an effective strategy in stem cell therapy(Gao et al., 2022) (Fig. 2).
In a variety of CNS diseases, inflammation is an important factor
causing the loss of nerve function, and is also the target of multiple drug
treatments(Dooley et al., 2014). For instance, in many animal models,
TNF-α and IFN-γ have been found to inhibit the proliferation of stem
cells(Ben-Hur et al., 2003). Anti-inflammatory drugs have shown sig­
nificant efficacy in promoting nerve regeneration by facilitating the
clearance of reactive oxygen species (ROS) and reducing the secretion of
inflammatory factors by macrophages(Gao et al., 2022).
Stem cells have demonstrated a positive response to inflammation, as
evidenced by studies highlighting the essential role of inflammation in
facilitating stem cell migration to injury sites(Kizil et al., 2015). In vitro
investigations have further revealed that inflammatory signals, such as
C. Ying et al.
Fig. 1. Neurotrophic effects of stem cells. Stem cells exert neuroprotective effects through the secretion of various growth factors, thereby enhancing their overall
neuroprotective potential. These growth factors have the capacity to influence different types of stem cells, regulating their proliferation and differentiation through
distinct signaling pathways. Simultaneously, these growth factors can also interact with the neural microenvironment, mediating neuroprotective effects by acti­
vating Trk receptors.
TNF-α or IL-1β, can stimulate stem cell proliferation via the activation of
NF-κB and JNK signaling pathways(Wang et al., 2007). Notably, TNF-α
knockout mice do not manifest the behavioral recovery observed in
wild-type mice following TBI(Scherbel et al., 1999). Intriguingly, the
downregulation of the anti-inflammatory factor IL-10 actually promotes
the differentiation of neural progenitor cells(Perez-Asensio et al., 2013).
Additionally, in zebrafish, inflammation has been identified as an active
regulator of CNS neuron regeneration(Kyritsis et al., 2012). Simply
inhibiting inflammatory reaction does not seem to be the best way to
promote nerve regeneration.
In conclusion, stem cell therapy for nerve regeneration should
consider the timing of intervention, the specific cytokines used, and the
regulatory scheme, as different cytokines can have varying effects on
NSCs at different times(Mueller et al., 2005).
3.1.3. Cell replacement
In addition to the various mechanisms mediated by neurotrophic
factor signaling pathways to protect and promote nerve recovery, stem
cells can also serve as cell substitutes themselves(Jiao et al., 2021)
(Fig. 3).
Some studies have demonstrated that following injury, a significant
influx of stem cells occurs at the injury site, where they undergo dif­
ferentiation into neurons, thereby inhibiting glial scar formation and cell
death(Song et al., 2015). Various markers indicative of neural differ­
entiation stages, such as Nestin, Tuj1, NeuN, TH, DARPP-32, and SV38,
have been detected in these migrating cells(Chang et al., 2013). Trans­
planted cells have been observed to differentiate into diverse neuronal
subtypes expressing GABA, parvalbumin, calretinin, or calbindin(Oki
et al., 2012).
However, previous studies have indicated that the neural function
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Experimental Neurology 369 (2023) 114543
recovery in experimental animals often occurs earlier than the time
required for the functional integration of transplanted stem cells, which
may be attributed to the rapid and highly spontaneous functional re­
covery observed in most experimental animals(Baker et al., 2019).
Nonetheless, it is widely believed that the long-term and effective cell
replacement achieved through stem cell therapy plays a crucial role in
the overall therapeutic outcome(Tornero et al., 2013).
Furthermore, it is possible to induce transplanted stem cells to
differentiate into specific subtypes of neurons, thereby enhancing the
therapeutic effects. For instance, inducing stem cells to differentiate into
dopaminergic neurons and transplanting them into Parkinson’s animal
model enhance the therapeutic effect(Hargus et al., 2010).
Stem cells provide a unique opportunity to reduce neurological
damage through multimodal treatment. Numerous preclinical studies
have demonstrated that stem cells exhibit neuroprotective effects by
mitigating secondary injury through anti-inflammatory mechanisms,
facilitating endogenous neurogenesis and synaptic remodeling, and
acting as cell substitutes to promote tissue and functional recovery
(Baker et al., 2019). Additionally, stem cell therapy promotes neural
function recovery by stimulating angiogenesis, facilitating blood-brain
barrier repair, and enhancing the formation of neural synapses(Kana­
zawa et al., 2017). These preclinical findings lay the groundwork for
further clinical research in this field.
3.2. Clinical findings of limitations of stem cell therapies for central
nervous system diseases
While stem cell therapy has demonstrated significant advantages in
preclinical research, progress in clinical studies has been somewhat
limited (Table.1). Stem cell therapy, whether delivered through arterial
C. Ying et al.
Fig. 2. The interaction between inflammatory immunity and stem cells. On the one hand, inflammation exerts a dual regulatory effect on stem cells. Various
chemokines and inflammatory mediators can modulate the migration, proliferation, and differentiation of stem cells. Additionally, the presence of reactive oxygen
species can induce apoptosis in both stem cells and neurons. On the other hand, stem cells themselves can influence different types of immune cells through various
mediators, either promoting or inhibiting the inflammatory response.
or intravenous injection or targeted transplantation, has been proved to
be safe by many clinical studies, but has little effect(Trounson and
McDonald, 2015).
Stem cell therapy holds great promise in the treatment of neurode­
generative diseases such as AD, where specific effective drugs are
currently lacking(Checkoway et al., 2011). Although preclinical studies
have studied the source, differentiation efficiency, culture method,
tumor formation, injection route and mobility of stem cells, and ach­
ieved satisfactory results, no significant clinical effects have been
observed in several clinical studies(Kang et al., 2016). Several factors,
including treatment timing, patient heterogeneity, and loss to follow-up,
can influence the outcomes of clinical research(Liu et al., 2020). More
clinical trials are in progress, and further steps are needed before stem
cell therapy becomes a clinically feasible method to treat related
diseases.
In the clinical research of nerve injury, stem cell therapy has not
yielded satisfactory results. While stem cell transplantation has gained
attention as a potential treatment for stroke, its clinical application re­
mains significantly limited(Zhao et al., 2022). Huo et al. conducted a
comprehensive analysis of clinical trials focused on stem cell trans­
plantation in stroke, and they concluded that there is currently insuffi­
cient evidence to support the replacement of damaged cells,
reconstruction of neural circuits, or improvement of functional loss
through stem cell transplantation after stroke(Huo et al., 2014). Fortu­
nately, most of the methods employed for stem cell transplantation
appear to be safe(Kawabori et al., 2020). To enhance the effectiveness of
6
Experimental Neurology 369 (2023) 114543
stem cell transplantation, further research is needed to determine
optimal parameters, including cell type, cell dosage, and injection
method.
4. Perspectives and challenges in stem cell therapies for central
nervous system diseases
4.1. Emerging trends in stem cell research for central nervous system
diseases
Based on the research on the mechanism of stem cell therapy and the
outcomes of clinical trials, it appears challenging to solely rely on stem
cell transplantation for direct promotion of nerve regeneration. There
are emerging trends in research related to stem cell therapy that warrant
discussion.
4.1.1. Stem cell acquisition
The acquisition of stem cells has been a prominent research focus in
stem cell therapy, especially with the emergence of iPSCs and induced
neural progenitor cells (iNPCs). iPSCs, derived from adult cells through
genetic reprogramming to exhibit properties akin to ESCs, possess the
capacity for differentiation into various cell types, including neurons.
(Aboul-Soud et al., 2021). iNPCs can be reprogrammed via astrocytes
through endothelial cell regulation or through the overexpression of
transcription factors, with different differentiation potential for
neuronal subtypes(Ma et al., 2018; Li et al., 2022). Researchers are
C. Ying et al.
Fig. 3. The cell replacement effect of stem cell therapy. In stem cell therapy for the central nervous system, various types of stem cells can express various neuronal
markers through pathways such as “migrate/transplantion” or “induced differentiation”, contributing to their role in cell replacement.
actively investigating the potential of induced pluripotent cells for
neural regeneration, as they can be derived from a patient’s own cells,
minimizing the risk of immune rejection(Du et al., 2022).
4.1.2. Gene editing
Gene editing has emerged as a valuable tool in stem cell therapy with
several applications. Firstly, it plays a crucial role in the conversion of
neurons into iPSCs(Tazaki et al., 2017). Gene editing techniques,
including CRISPR/Cas9, are employed to modify stem cells, enhancing
their potential for neural regeneration(Yang et al., 2022). Secondly,
researchers are utilizing gene editing to rectify genetic mutations asso­
ciated with neurological disorders, such as Huntington’s disease(Golas
and Sander, 2016). Furthermore, gene editing can empower stem cells to
secrete specific neurotrophic factors like BDNF, thereby promoting
neuronal regeneration(Deng et al., 2016).
4.1.3. 3D bioprinting
3D bioprinting technology is being employed to fabricate brain-like
structures, mimicking the intricate complexity of the human brain. By
utilizing different types of 3D biomaterials, such as scaffolds, the neural
microenvironment surrounding stem cells can be regulated, effectively
guiding their growth and differentiation(Koffler et al., 2019). Integra­
tion of stem cell transplantation with 3D biomaterials holds promise in
promoting nerve regeneration and augmenting the efficacy of stem cell
therapy(Chen et al., 2022).
7
Experimental Neurology 369 (2023) 114543
4.1.4. Combination therapies
Researchers are actively investigating combination therapies that
combine stem cells with other modalities, including drugs and physical
therapy, to enhance treatment outcomes(Lukovic et al., 2015). For
instance, the combination of stem cell transplantation with rehabilita­
tion therapy or electromagnetic stimulation has shown promise in pro­
moting the repair of SCI(Zheng et al., 2020; Lu et al., 2022).
4.1.5. Anti immune rejection
Due to the immune rejection in stem cell transplantation, researchers
are attempting to reduce its adverse effects from multiple perspectives.
MSCs inhibit T and B cell activity and can be used to suppress immune
mediated diseases and transplant rejection reactions(Uccelli et al.,
2007). Compared to NSCs transplantation, MSCs transplantation elicits
weaker immune responses and provides long-term behavioral benefits
(Rossignol et al., 2014). Additionally, biomaterials such as hydrogels are
being investigated to modulate the immune microenvironment post-
implantation, enhancing the survival and functionality of stem cells,
and working in conjunction with immunosuppressive drugs to regulate
immune rejection(Gao et al., 2023).
Overall, the emerging trends in stem cell research for neural regen­
eration show great promise in the development of novel treatments for
neurological disorders and injuries. However, it is important to
emphasize the need for further research to comprehensively evaluate
the safety and efficacy of these therapies. Continued investigation and
rigorous clinical trials will be essential to ensure the successful
C. Ying et al. Experimental Neurology 369 (2023) 114543

Table 1 cells(Gao et al., 2023). To mitigate the risk of immune rejection, re­
Summary of stem cells administered in clinical trials in the last 10 years. searchers are actively investigating diverse strategies, including the
Disease Stem Routes No. Outcome Reference utilization of patient-specific stem cells and immune suppression ther­
Target cell cases apy(Rosenzweig et al., 2018). While there is a foundation of research in
types the field of immune rejection, further studies are warranted to enhance
AD hUCB- Stereotactic 9/9 No adverse (Kim et al., its application in the context of stem cell therapy(Uccelli et al., 2007;
MSCs brain injection events; 2015) Rossignol et al., 2014; Gao et al., 2023).
No dose-
limiting
toxicity;
4.2.2. Tumor formation
No Tumorigenicity and pluripotent differentiation potential are coupled
improvement cell properties unified by neural stemness(Zhang et al., 2022). There­
ALS MSCs Intrathecal 19/ No adverse (Petrou fore, there is a risk of tumor formation associated with stem cell thera­
injection 19 events; et al.,
pies(Johnson et al., 2008; Ritfeld et al., 2011). Although some clinical
Some patients 2021)
had a > 25% trials have not found that transplanted NSCs are associated with tumor
improvement formation, more clinical research data are needed to assess the safety of
IS AD- Intravenous 4/13 No adverse (de Celis- treatment before large-scale clinical application(Yan et al., 2013; Chang
MSCs injection events; Ruiz et al., et al., 2013; Lee et al., 2016).
No tumor 2022)
formation;
No 4.2.3. Regulatory approval
improvement Stem cell therapies for neural regeneration encounter significant
ALS hNSCs Microinjections 18/ No adverse (Mazzini regulatory challenges pertaining to safety, efficacy, and ethical aspects
into the gray 18 events; et al.,
(Sonntag et al., 2018). The regulatory approval process is multifaceted,
matter tracts No tumor 2019)
formation; necessitating comprehensive preclinical and clinical investigations
Limited while ensuring adherence to ethical standards and regulatory
efficacy guidelines.
IS ABMD- Intravenous 16/ No adverse (Jaillard In summary, the resolution of these technical challenges is of utmost
MSCs injection 31 events; et al.,
importance in the advancement of safe and effective stem cell therapies
No 2020)
improvement for nerve regeneration. While there is still much work to be done,
in neurological ongoing research endeavors are making significant strides in tackling
function score; these obstacles and bringing stem cell therapies closer to real-world
Improvement
clinical applications.
in motor
function score
SCI AD- Intrathecal 1/1 No adverse (Bydon 4.3. Ethical considerations for stem cell therapies
MSCs injection events; et al.,
Meaningful 2020) The clinical application of stem cell therapy requires serious
improvement
SCI hiPSC- Intrathecal 4/4 Not yet (Sugai
consideration of ethical issues. The ethical considerations mainly
NS/PC injection completed; et al., include the following aspects.
To evaluate 2021) Source of stem cells: The source of stem cells is a significant ethical
safety consideration. ESCs, which are derived from human embryos, are highly
IS hNSCs Stereotactic 11/ No adverse (Kalladka
pluripotent and have the potential to develop into any cell type in the
ipsilateral 13 events; et al.,
putamen Decreased 2016) body. However, the use of ESCs raises ethical concerns related to the
injection infarct destruction of human embryos(Sugaya and Vaidya, 2018). The research
of iPSCs does not involve corresponding ethical issues, which is a po­
Abbreviations: No. cases: number of cases in the treatment group/total number
of cases; hUCB-MSCs: human umbilical cord blood-derived mesenchymal stem
tential alternative(Du et al., 2022).
cells; AD-MSCs: adipose tissue-derived mesenchymal stem cells. Informed consent: Informed consent is an essential ethical consid­
IS: Ischemic Stroke; hNSCs: human neural stem cells; ABMD-MSCs: autologous eration for any medical procedure, including stem cell therapies. Pa­
bone marrow-derived mesenchymal stem cells; hiPSC-NS/PC: induced pluripo­ tients must be fully informed of the risks and benefits of stem cell
tent cell-derived neural stem/progenitor cell. therapies and must provide informed consent before treatment.
Fairness and access: The availability and affordability of stem cell
translation of these advancements into effective and reliable treatments therapies can raise concerns about fairness and access. Stem cell thera­
for patients. pies are often expensive and may not be accessible to all patients,
leading to potential disparities in access to treatment.
In summary, careful consideration of ethical issues is crucial to
4.2. Technical challenges in stem cell therapies for central nervous system ensuring that stem cell therapies are developed and used in a responsible
diseases and ethical manner.

Based on the results of current clinical research, although stem cell
therapies hold promise for neural regeneration, there are several tech­
nical challenges that need to be addressed before these therapies can be
widely used in clinical settings(Chang et al., 2020).
4.2.1. Immune rejection
Immune rejection poses a significant challenge in stem cell trans­
plantation treatments, affecting their overall efficacy and success
(Sackett et al., 2016). The transplantation of stem cells can activate
immune responses that may result in the rejection of the transplanted
5. Conclusion
Stem cell therapies for neural regeneration hold tremendous poten­
tial in the treatment of CNS diseases and injuries. Extensive preclinical
and clinical studies have utilized various types of stem cells, each with
their own advantages and limitations. These therapies have shown
promise in addressing conditions like PD, stroke, and SCI, shedding light
on the underlying molecular mechanisms of neural regeneration.
However, technical limitations, ethical considerations, and regulatory
challenges still need to be addressed to advance this field further.

8
C. Ying et al.
Encouragingly, emerging trends in gene editing and tissue engineering
present opportunities for overcoming these obstacles. Ongoing research
is essential to enhance the safety and efficacy of stem cell therapies while
ensuring a thoughtful exploration of their ethical implications.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and materials
Not applicable.
Funding
This study was supported by the National Natural Science Founda­
tion of China (81870964) and Zhejiang Provincial Natural Science
Foundation of China (LY23H090012). The funding body played no role
in the design of the study and collection, analysis, and interpretation of
data and in writing the manuscript.
Authors’ contributions
CY and JZ contributed to literature collection and drafting the
manuscript. HZ contributed to manuscript and figures revisions during
the revision work period. SG contributed to design of figures and tables.
XG and JL collected the literatures. YH and HW designed the study and
critically revised the manuscript. All authors contributed to the article
and approved the submitted version.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Data availability
No data was used for the research described in the article.
Acknowledgements
Not Applicable.
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