Stem-cell therapies for stroke promise a hope because they are neuroprotective and regenerative. Stroke stem cell therapies target the process of neuroregeneration, neuronal resection, and brain neurons during the critical period of stroke to avoid the dispersal of damage. Different types of stem cells, including mesenchymal stem cells, induced pluripotent stem cells, embryonic stem cells, and neural stem cells, have been extensively studied.

Fig.1. Stem cell therapy as a promising approach for ischemic stroke treatment. (Yaqubi, et al., 2024)

As a stroke-focused CRO, Ace Therapeutics is dedicated to helping clients develop stem cell-based therapies for stroke. Our multidisciplinary team of experts includes neuroscientists, cell biologists, and biomedical engineers, who work closely with clients to design and implement customized preclinical studies of stem cell-based therapies for stroke.

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• Development of Stem Cell-Based Therapy for Stroke

Cell Types for Stroke

Stem cells regenerate themselves and divide into many cell types. Many different cell types from neural and non-neural tissues have been studied in animals or humans for recovery from stroke. Different study groups have validated the use of stem cells in terms of various parameters, including stem cell type, number/dose of stem cells, administration method, stem cell homing and tracking, and stem cell safety and effectiveness.

Fig.2. Functional recovery and differentiation of multilineage-differentiating stress-enduring (Muse) cells into neuronal-lineage cells are observed when transplanted intravenously into lacunar stroke mouse models. (Park, et al., 2020)

Potential Mechanisms for Cell Therapy Enhancing Recovery in Stroke

Stem cell-based therapies are very promising as stroke therapies, given their long-term target window, variety of action mechanisms, and adaptedness to the environment. In the early days, cell therapy was devoted to restoring destroyed neuronal cells and circuits. But now it's about harnessing stem cells for trophic support and activating endogenous repair. It has been demonstrated that stroke is functionally restored in animal stroke models without the long-term survival of the transplanted cells and that it is mediated through indirect means: trophic maintenance, angiogenesis, increased neurogenesis, and inflammation suppression.

Trophic Support

Trophic factors such as VEGF, NGF, and BDNF are critical for vascular and neuronal growth in the CNS. Following ischemia, these factors are naturally upregulated, and their exogenous administration has shown benefits in animal models. Cellular therapies, particularly using MSCs, enhance the secretion of trophic factors like VEGF, contributing to improved recovery, smaller infarcts, and increased vascular and neuronal support in ischemic models.

Promotion of Angiogenesis

Following a stroke, an innate angiogenic response occurs in the ischemic border, characterized by collateral growth, increased reperfusion, and endothelial cell proliferation, peaking at 7 days in rodents. Enhanced angiogenesis benefits ischemic stroke therapy by improving blood flow, reducing infarct volume, and supporting neural vascular networks for faster recovery. It may also mitigate post-ischemic dementia by improving blood flow in non-infarcted brain regions.

MSCs have shown significant potential in promoting angiogenesis across various models. Studies have demonstrated increased capillary density and blood flow after MSC transplantation in ischemic models, including rodent models of stroke, myocardial infarction, and hindlimb ischemia.

Modulation of Endogenous Neurogenesis

The adult CNS can create new neurons and glia from precursor cells, in particular in the SVZ, a very pertinent part of the brain in the event of cerebral ischemia. Stroke increases the SVZ's neurogenesis, and a deviant NPC is diverted from its normal trajectory to the smell bulb to the infarct. But the life of these NPCs, and the number of lost neurons they can substitute for, is limited.

Neurogenesis and NPC migration are regulated by cytokines and chemotactic gradients, such as the CXCR4/SDF-1α axis, which attracts NPCs to ischemic regions. Enhancing these gradients could improve NPC survival and efficacy. Strategies like administering cytokines, growth factors, small molecules, environmental enrichment, peripheral stimulation, or exogenous cell transplantation have shown a potential to boost endogenous neurogenesis post-ischemia.

Immune Modulation

The role of immune modulation in stroke repair could benefit therapies that target suppressing pro-inflammatory mediators and promoting anti-inflammatory mediators. Exogenous stem cell transplantation can regulate ischemia-induced neuroinflammation. For example, in rodent models, iPSCs plus fibrin glue reduced pro-inflammatory cytokines and increased anti-inflammatory cytokine production a week after transplantation.

Fig.3. Mechanisms of action of mesenchymal stem cells in treating stroke. (Singh, et al., 2020)

Challenges of Stroke Treatment With Stem Cell Therapy

Many hurdles must be overcome before successful application of stem cells in the clinic. Tracking transplanted cells in vivo is possible through imaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). Strategies like using hyaluronic acid (HA) hydrogels can improve cell survival and enable tracking via MRI. Ethical issues (such as embryonic and neural stem cell risks) can be alleviated using iPSCs, but creating autologous iPSCs is time-consuming and expensive.

Safety concerns include immune rejection in allografts, potential tumorigenesis from undifferentiated stem cells, and the risk of undesirable tissue differentiation. For example, undifferentiated ESCs can lead to tumor growth, and donor-derived NSC transplants have been linked to brain tumors in rare cases. Further research is needed to optimize transplantation strategies, including timing, routes, and dosages, to ensure safety and efficacy.

1. Yaqubi, S., & Karimian, M. (2024). Stem cell therapy as a promising approach for ischemic stroke treatment. Current Research in Pharmacology and Drug Discovery, 100183.
2. Park, Y. J., et al. (2020). Cell-based therapy for stroke: musing with muse cells. Stroke, 51(9), 2854-2862.
3. Singh, M., et al. (2020). Application of stem cells in stroke: a multifactorial approach. Frontiers in Neuroscience, 14, 473.