Nagpur college of pharmacy, Wanadongri, Nagpur.
Stroke is a major global health concern and a leading cause of death and long-term disability worldwide. A large number of stroke survivors continue to face life-altering impairments, resulting in a high mortality rate. Given these challenges, there is increasing interest in regenerative medicine approaches, particularly stem cell therapies, which hold promise for repairing damaged brain tissue and enhancing functional recovery. This review aims to provide a comprehensive overview of the current research on stem cell therapy for stroke, discussing the biological rationale, types of stem cells used, underlying mechanisms, preclinical and clinical evidence, challenges, and future directions.
Stroke is a major global health concern and a leading cause of death and long-term disability worldwide (1). Approximately 85% of strokes are ischemic, caused by the blockage of blood flow to parts of the brain, which often results in irreversible neurological damage (2). While current treatments, such as thrombolysis and mechanical thrombectomy, have improved acute stroke management, they are limited by narrow treatment windows and cannot fully restore lost brain functions for many patients (3). Consequently, a large number of stroke survivors continue to face life-altering impairments. Given these challenges, there is increasing interest in regenerative medicine approaches, particularly stem cell therapies, which hold promise for repairing damaged brain tissue and enhancing functional recovery (4). Stem cells can potentially replace injured neurons, reduce harmful inflammation, and stimulate the brain’s intrinsic repair mechanisms (5). This review aims to provide a comprehensive overview of the current research on stem cell therapy for stroke, discussing the biological rationale, types of stem cells used, underlying mechanisms, preclinical and clinical evidence, challenges, and future directions (6).
Pathophysiology Of Stroke:
Stroke is broadly divided into two main types: ischemic and hemorrhagic. Ischemic stroke, responsible for about 85% of cases, occurs due to a blockage in cerebral blood vessels, typically from a thrombus or embolus, leading to reduced blood flow and oxygen deprivation in affected brain regions. Hemorrhagic stroke, on the other hand, results from rupture of blood vessels causing bleeding into brain tissue, which increases intracranial pressure and damages neurons (7).
At the cellular and molecular level, ischemia sets off a cascade of deleterious events. Oxygen and glucose deprivation cause energy failure, excitotoxicity due to excessive glutamate release, oxidative stress, and disruption of the blood-brain barrier. These lead to neuronal death mainly via necrosis and apoptosis (8). The brain’s innate response involves activation of microglia and infiltration of peripheral immune cells, resulting in neuroinflammation which, while aiming to clear damage, can exacerbate injury if uncontrolled (9).
Following this, neurodegenerative processes progress over days to weeks, contributing to ongoing functional deficits. Although endogenous repair mechanisms such as angiogenesis, neurogenesis, and synaptic plasticity are activated, their extent is generally insufficient to fully restore damaged neural networks (10).
Types Of Stem Cells Used In Therapy:
Stem cell-based therapy for stroke involves a variety of stem cell types, each with unique characteristics, advantages, and challenges. Understanding these cell types is fundamental to appreciating their therapeutic potential.
Neural Stem Cells (NSCs)
NSCs are multipotent cells capable of differentiating into the major neural lineages: neurons, astrocytes, and oligodendrocytes. They are naturally present in certain brain regions and have intrinsic neurogenic potential. NSCs can potentially replace lost neurons and support synaptic network reconstruction. However, their clinical use is limited by difficulties in sourcing sufficient quantities, ethical concerns when derived from fetal tissue, and risks such as tumor formation (11).
Mesenchymal Stem Cells (MSCs)
MSCs are among the most extensively studied for stroke therapy due to their accessibility, immunomodulatory properties, and safety profile. They can be isolated from bone marrow, adipose tissue, umbilical cord, and dental pulp. MSCs primarily exert their effects through paracrine signaling, secreting trophic factors that modulate inflammation, promote angiogenesis, and encourage endogenous repair rather than direct neuronal replacement (12).
Induced Pluripotent Stem Cells (iPSCs)
iPSCs are generated by reprogramming somatic cells to a pluripotent state, enabling differentiation into any cell type. They offer the advantage of providing autologous cell sources, reducing immune rejection issues. Despite their promise, concerns remain about tumorigenicity, genomic instability, and complex manufacturing requirements (13).
Embryonic Stem Cells (ESCs)
ESCs possess robust pluripotency and high proliferation capacity. They can differentiate into neural cells but are rarely used clinically due to ethical controversies and significant tumorigenic risks. Additionally, immunological incompatibility poses challenges for transplantation (14).
Other Stem Cell Types
Other sources include hematopoietic stem cells (HSCs), endothelial progenitor cells, and pericyte-derived stem cells, each investigated for specific therapeutic roles such as vascular repair or immunomodulation in stroke (15).
Mechanism Of Stem Cell Therapy In Stroke:
Stem cell therapy benefits stroke recovery through multiple, often interconnected mechanisms that work synergistically to repair brain tissue, reduce damage, and enhance functional restoration.
Cell Replacement and Neural Regeneration
Stem cells can differentiate into neurons and glial cells, potentially replacing the cells lost during stroke-induced ischemia or hemorrhage. Neural stem cells and pluripotent stem cells especially show capacity to integrate and form synaptic connections, though in vivo functional replacement remains challenging and limited so far (16)
Comparison of Stem Cell Types for Stroke Therapy:
|
Stem Cell Type |
Source |
Advantages |
Disadvantages |
Differentiation Potential |
Clinical Safety |
Therapeutic Mechanisms |
|
Mesenchymal Stem Cells (MSCs) |
Bone marrow, adipose tissue, umbilical cord |
High safety profile, immunomodulatory properties, easy isolation, no tumorigenicity risk |
Limited neural differentiation capability, variable efficacy |
Moderate - can differentiate into neurons, astrocytes, oligodendrocytes |
Excellent - well-tolerated in clinical trials |
Paracrine signaling, immunomodulation, anti-inflammatory effects, angiogenesis promotion |
|
Neural Stem Cells (NSCs) |
Fetal brain tissue, adult brain niches |
Direct neural differentiation, high integration potential, neuronal replacement |
Ethical concerns with fetal sources, limited availability, complex isolation |
High - naturally differentiate into neurons, astrocytes, oligodendrocytes |
Good - generally safe but limited clinical data |
Direct cell replacement, neural network integration, endogenous repair stimulation |
|
Induced Pluripotent Stem Cells (iPSCs) |
Reprogrammed somatic cells (skin, blood) |
Autologous source eliminating immune rejection, unlimited proliferation, patient-specific therapy |
Tumorigenicity risk, complex manufacturing process, regulatory challenges |
Very High - pluripotent with capacity for all neural cell types |
Moderate - tumorigenic potential requires careful monitoring |
Neural differentiation, paracrine effects, neuroprotection, personalized treatment |
|
Embryonic Stem Cells (ESCs) |
Embryonic blastocyst tissue |
Highest differentiation potential, unlimited self-renewal, proven pluripotency |
Major ethical concerns, immune rejection risk, tumorigenicity |
Very High - true pluripotency for all cell types |
Low - ethical and safety concerns limit clinical use |
Neural replacement, growth factor secretion, developmental pathway activation |
|
Adipose-Derived Stem Cells (ADSCs) |
Subcutaneous fat tissue |
Easy and safe harvest, abundant source, minimal invasive procedure |
Lower neural differentiation than NSCs, variable potency |
Moderate - mesenchymal lineage with limited neural potential |
Excellent - minimal adverse events reported |
Anti-inflammatory, angiogenesis, paracrine signaling, tissue repair |
Paracrine Effects
A primary mechanism is the secretion of growth factors, cytokines, chemokines, and extracellular vesicles such as exosomes by transplanted cells. These factors diminish apoptosis, stimulate endogenous neurogenesis, support angiogenesis, and modulate the extracellular matrix to create a reparative niche. (17)
Immunomodulation
Stem cells, especially mesenchymal stem cells, can modulate the neuroinflammatory response post-stroke, reducing the infiltration and activation of damaging immune cells while promoting beneficial microglial phenotypes. This dampens secondary injury and supports recovery (18).
Angiogenesis and Vascular Repair
Stem cell therapies promote formation of new blood vessels and repair damaged endothelium, improving oxygen and nutrient delivery to ischemic tissues. Secreted angiogenic factors like VEGF (vascular endothelial growth factor) facilitate this process, which is crucial for brain tissue remodeling and function (19).
Synaptic Plasticity and Neural Network Remodeling
Stem cells may enhance synaptic connectivity and plasticity, enabling rewiring of surviving neural circuits. This encourages compensatory functional recovery and learning after damage (20).
Preclinical Studies and Animal Models:
Preclinical studies using animal models are essential for understanding the efficacy and mechanisms of stem cell therapy before clinical application in humans. Rodent models, especially middle cerebral artery occlusion (MCAO), are the most widely employed for ischemic stroke research due to their reproducibility and similarity to human stroke pathology (21).
These models have demonstrated that stem cell therapy can significantly reduce infarct size, promote neuronal survival, and improve motor and cognitive functions (22). Transplanted stem cells migrate to the injury site, secrete neurotrophic factors, and modulate immune responses. Various delivery routes such as intravenous, intra-arterial, and intracerebral injections have been tested, each with distinct advantages and limitations (23).
Despite promising results, translating outcomes from animal studies to clinical success remains challenging due to interspecies differences, variability in stem cell sources, dosages, timing of administration, and outcome measures Standardization of protocols and larger animal models are needed to better predict human responses (24).
Clinical Trials of Stem Cell Therapy for Stroke:
Clinical trials assessing stem cell therapies in stroke patients have primarily focused on evaluating safety and preliminary efficacy. To date, multiple early-phase studies report that various stem cell types are generally safe and well tolerated, regardless of the delivery method used, including intravenous, intra-arterial, and intracerebral routes (25).
Some clinical trials, especially those involving mesenchymal stem cells (MSCs), have documented modest but encouraging improvements in neurological function, motor skills, and quality of life, particularly in patients during the chronic phase post-stroke (26). The timing of stem cell administration appears critical—earlier intervention may enhance therapeutic benefits—although results across trials differ due to design variability (27). Moreover, researchers continue to investigate optimal cell sources, dosages, and delivery techniques to maximize efficacy (28).
Despite these promising findings, the current evidence base is limited by small sample sizes, heterogeneity in study protocols, and short follow-up durations. To establish stem cell therapy as a standard treatment, larger, well-designed randomized controlled trials with standardized outcome assessments are imperative (29).
Challenges and Limitations:
Despite significant progress in stem cell research for stroke, several critical challenges and limitations hinder its widespread clinical application.
Timing and Dosage
Determining the optimal timing for stem cell administration remains a major challenge. Early intervention post-stroke may promote better outcomes, but the inflammatory environment and ongoing tissue damage can also reduce cell survival. In contrast, delayed treatments face limited regenerative capacity. Furthermore, the ideal cell dose is not clearly established, with inconsistent dosing regimens across studies complicating comparison (30).
Immune Rejection and Safety
While mesenchymal stem cells (MSCs) exhibit relative immunoprivilege, allogeneic cells can still elicit immune responses that may reduce efficacy or cause adverse effects. Autologous therapies bypass this but can be difficult to obtain promptly. The potential for tumor formation, especially with pluripotent stem cells like ESCs and iPSCs, poses a serious safety concern (31).
Ethical and Regulatory Issues
Use of embryonic stem cells raises ethical controversies that restrict research and clinical use in many regions. Regulatory landscapes vary globally, complicating multi-center trials and approvals. Ensuring quality control in stem cell products is paramount to patient safety (32).
Scalability and Cost
Producing clinically relevant quantities of stem cells while maintaining consistency and functionality is challenging and expensive. Manufacturing, storage, and delivery logistics limit access and affordability, especially in low-resource settings (33).
Standardization and Traceability
Heterogeneity in cell sources, preparation methods, delivery routes, and outcome metrics across studies hampers direct comparison and meta-analyses. Lack of standardized protocols and difficulty in tracking transplanted cell fate frustrate efforts to establish definitive efficacy (34).
Recent Advances and Innovations:
Exciting advances in stem cell therapy for stroke hold promise to improve outcomes and address many previous limitations.
Gene Editing and Modified Stem Cells
Current research focuses on genetically engineering stem cells to enhance survival, targeting capability, and therapeutic factor secretion. For example, CRISPR-Cas9 technology is being used to create universal donor cells, reduce immunogenicity, and boost neuroprotective properties (35).
Biomaterials and Scaffolds
The integration of biomaterials such as hydrogels, collagen matrices, and three-dimensional scaffolds enables more efficient delivery and engraftment of stem cells in the injured brain. These biomaterials can provide structural support and controlled release of beneficial agents, improving cell survival and integration (36).
Exosome-Based and Cell-Free Therapies
Recent studies show that exosomes—small vesicles secreted by stem cells—carry many of the regenerative and immunomodulatory benefits without the need to transplant live cells. Exosome therapy may offer a safer, more scalable alternative that avoids tumorigenicity and immune complications (37).
Combination Therapies
Combining stem cell transplantation with rehabilitation, pharmacological agents, or neuroprotective compounds has become increasingly prominent. Such strategies may leverage synergistic effects, further enhancing functional recovery and brain repair (38).
Personalized Medicine and Advanced Imaging
Personalized approaches using patient-derived iPSCs, advanced cell selection, and real-time neuroimaging to monitor graft survival and function are being developed. These strategies improve the predictability and safety of stem cell interventions in stroke care (39).
Future Directions:
The future of stem cell therapy for stroke is shaped by rapid innovation and expanding interdisciplinary collaboration (40). Key developments are likely to improve treatment efficacy, safety, personalization, and accessibility.
Advances in gene editing, particularly CRISPR-based approaches, are driving the creation of universal donor stem cells with reduced immunogenicity and enhanced reparative properties, thus allowing for off-the-shelf therapies that bypass many ethical and logistical hurdles (41). Ongoing efforts to standardize protocols for cell preparation, delivery, and monitoring are essential for consistent outcomes across clinical settings (42). Integration with advanced imaging and biomarker analysis enables real-time tracking of transplanted cells and more precise patient stratification.
This may lead to more personalized treatments tailored to the patient’s genetic and clinical profile, maximizing therapeutic gain while minimizing risks (43). Artificial intelligence (AI) and machine learning are increasingly applied in analyzing data from preclinical and clinical studies to optimize patient selection, predict treatment response, and identify ideal intervention windows (44).
Cell-free therapies, such as the use of extracellular vesicles or exosomes derived from stem cells, are being actively investigated as a means to deliver regenerative cues with lower safety risks and greater scalability (45).
Combination therapies—pairing stem cell transplants with pharmacological agents or advanced rehabilitation—may produce synergistic effects, leading to more robust recovery than either approach alone (46).
Ultimately, large-scale, multicenter clinical trials with harmonized outcome measures and longer follow-up periods are urgently needed to definitively establish the efficacy and long-term safety of stem cell-based interventions in stroke recovery (47).
CONCLUSION:
Stem cell therapy stands at the forefront of innovation in stroke treatment, offering new hope where conventional therapies too often fall short. Extensive laboratory and early clinical research suggest that stem cells have the potential to repair damaged neural networks, dampen harmful inflammation, and foster meaningful neurological recovery.
The field has benefitted from rapid advances in cell engineering, biomaterials, imaging, and data analytics, each contributing to safer, more effective, and more personalized therapeutic strategies. Looking ahead, the combination of scientific rigor, technological innovation, and global collaboration is essential for translating laboratory promise into everyday clinical benefit. With continued progress, stem cell-based interventions are increasingly likely to become a key part of restorative care in stroke, improving recovery and quality of life for countless patients worldwide
REFERENCES
Parth Jibhakate*, Arya Gujarkar, Stem Cell Therapy for Stroke: A New Frontier in Neurodegenerative Medicines, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 11, 688-697 https://doi.org/10.5281/zenodo.17532228
10.5281/zenodo.17532228
