Gene and Stem Cell Therapy in Ischemic Stroke

Possible strategies for treating ischemic stroke include neuroprotection (preventing injured neurons from undergoing apoptosis in the acute phase of cerebral ischemia) and stem cell therapy (the repair of disrupted neuronal networks with newly born neurons in the chronic phase of cerebral ischemia). First, we estimated the neuroprotective effect of glial cell line-derived neurotrophic factor (GDNF) by administration of GFNF protein. GDNF protein showed a direct protective effect against ischemic brain damage. Pretreatment of animals with adenoviral vector containing GDNF gene (Ad-GDNF) 24 h before the subsequent transient middle cerebral artery occlusion (MCAO) effectively reduced infarcted volume. Secondly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin. Both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their antioxidative property. Lastly, we developed a restorative stroke therapy with a bioaffinitive scaffold, which is able to provide an appropriate platform for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

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Potential Mechanisms and Perspectives in Ischemic Stroke Treatment Using Stem Cell Therapies

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.646927 ◽

2021 ◽

Vol 9 ◽

Author(s):

Guoyang Zhou ◽

Yongjie Wang ◽

Shiqi Gao ◽

Xiongjie Fu ◽

Yang Cao ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Ischemic Stroke ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Protective Factor ◽

Neural Circuit ◽

Chronic Phase ◽

Cell Types ◽

Stroke Treatment

Ischemic stroke (IS) remains one of the major causes of death and disability due to the limited ability of central nervous system cells to regenerate and differentiate. Although several advances have been made in stroke therapies in the last decades, there are only a few approaches available to improve IS outcome. In the acute phase of IS, mechanical thrombectomy and the administration of tissue plasminogen activator have been widely used, while aspirin or clopidogrel represents the main therapy used in the subacute or chronic phase. However, in most cases, stroke patients fail to achieve satisfactory functional recovery under the treatments mentioned above. Recently, cell therapy, especially stem cell therapy, has been considered as a novel and potential therapeutic strategy to improve stroke outcome through mechanisms, including cell differentiation, cell replacement, immunomodulation, neural circuit reconstruction, and protective factor release. Different stem cell types, such as mesenchymal stem cells, marrow mononuclear cells, and neural stem cells, have also been considered for stroke therapy. In recent years, many clinical and preclinical studies on cell therapy have been carried out, and numerous results have shown that cell therapy has bright prospects in the treatment of stroke. However, some cell therapy issues are not yet fully understood, such as its optimal parameters including cell type choice, cell doses, and injection routes; therefore, a closer relationship between basic and clinical research is needed. In this review, the role of cell therapy in stroke treatment and its mechanisms was summarized, as well as the function of different stem cell types in stroke treatment and the clinical trials using stem cell therapy to cure stroke, to reveal future insights on stroke-related cell therapy, and to guide further studies.

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Stem cell therapy in ischemic stroke: A systematic review and meta-analysis of randomized controlled trials

Annals of Indian Academy of Neurology ◽

10.4103/aian.aian_384_20 ◽

2021 ◽

Vol 0 (0) ◽

pp. 0

Author(s):

Kameshwar Prasad ◽

Amit Kumar ◽

Dimple Rawat

Keyword(s):

Systematic Review ◽

Stem Cell ◽

Ischemic Stroke ◽

Cell Therapy ◽

Randomized Controlled Trials ◽

Stem Cell Therapy ◽

Meta Analysis ◽

Controlled Trials ◽

Randomized Controlled

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Optimizing Stem Cell Therapy after Ischemic Brain Injury

Journal of Stroke ◽

10.5853/jos.2019.03048 ◽

2020 ◽

Vol 22 (3) ◽

pp. 286-305 ◽

Cited By ~ 1

Author(s):

Shuai Zhang ◽

Brittany Bolduc Lachance ◽

Bilal Moiz ◽

Xiaofeng Jia

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Cardiac Arrest ◽

Stem Cell ◽

Brain Injury ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Injury Treatment

Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and in vivo potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.

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A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies

Current Neuropharmacology ◽

10.2174/1570159x19666210907092928 ◽

2021 ◽

Vol 19 ◽

Author(s):

Aditya A Singh ◽

Akash Kharwar ◽

Manoj P. Dandekar

Keyword(s):

Stem Cell ◽

Ischemic Stroke ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Neurotrophic Factors ◽

Treatment Strategies ◽

Experimental Models ◽

Cerebral Stroke ◽

Post Stroke ◽

Stroke Models

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

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Abstract TP401: Inflated Expectations about Stem Cell Therapy in Patients With Chronic Stroke

Stroke ◽

10.1161/str.44.suppl_1.atp401 ◽

2013 ◽

Vol 44 (suppl_1) ◽

Author(s):

Jinho Lee ◽

Kyu-Yong Lee ◽

Young-Seo Kim ◽

Hyun Young Kim ◽

Hyuk Sung Kwon ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Ischemic Stroke ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Chronic Stroke ◽

Accurate Information ◽

Stroke Patients ◽

Media Channels ◽

Source Of Information

Introduction: Stem cell therapy (SCT) has been proposed for the treatment of neurological disorders. Although there isinsufficient clinical evidence to support its efficacy, unproven SCTs are being performed worldwide. Hypothesis: In this study, we investigated the perspectives and expectations of chronic ischemic stroke patients and physicians about SCTs. Methods: A total of 250 chronic ischemic stroke patients were interviewed at 4 hospitals. Structured open and closed questions about SCT for chronic stroke were asked by trained interviewers using the conventional in-person method. In addition, 250 stroke-related physicians were randomly interviewed via an e-mail questionnaire. Results: Of the 250 patients (mean 63 years, 70% male), 121 (46%) responded that they wanted to receive SCT in spite of its unknown side effects. Around 60% of the patients anticipated physical, emotional, and psychological improvement after SCT, and 158 (63%) believed that SCT might prevent strokes. However, physicians had much lower expectations about the effectiveness of SCTs, which was not in line with patient expectations. Multivariate analysis revealed that male gender (OR: 2.00, 95% CI: 1.10-3.64), longer disease duration (OR: 1.01, 95% CI:1.00-1.02), higher modified Rankin Scale score (OR: 1.30, 95% CI 1.06-1.60), and familiarity with stem cells (OR: 1.86, 95% CI: 1.10-3.15) were independently associated with wanting SCT. The major source of information about SCT was television (68%), and the most reliable source was physicians (49%). Conclusion: Patients have unfounded expectations that SCT will improve their functioning. Considering our finding that the major source of information on stem cells is media channels but not the physician, to decrease patients’ inappropriate exposure, doctors should make more effort to educate patients using mass media with accurate information.

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