Dr Teoh – Family Medicine Specialist, Stem Cell & Immune Therapy

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Management of Ischemic Stroke and the Role of Mesenchymal Stem Cells (MSC)

4–6 minutes

Introduction

Ischemic stroke is a major cause of morbidity and mortality worldwide. Immediate and effective management is crucial to improving outcomes. Recent advancements in mesenchymal stem cell (MSC) therapy offer promising adjunctive treatments for enhancing recovery post-stroke. This article outlines the standard management of ischemic stroke and explores the role and timing of MSC therapy in improving patient outcomes.

Management of Ischemic Stroke

1. Immediate Treatment:

  • Thrombolysis: Administer intravenous tissue plasminogen activator (tPA) within 4.5 hours of symptom onset to dissolve the clot and restore blood flow.
  • Mechanical Thrombectomy: For patients with large vessel occlusion, endovascular procedures to remove the clot can be performed up to 24 hours after symptom onset, depending on the patient’s condition and imaging findings.

2. Acute Management:

  • Antiplatelet Therapy: Administer aspirin or other antiplatelet agents to prevent further clot formation.
  • Anticoagulation: For patients with atrial fibrillation or other conditions predisposing to clot formation, anticoagulants such as warfarin or direct oral anticoagulants (DOACs) may be prescribed.
  • Blood Pressure Control: Manage blood pressure to prevent further vascular damage. However, overly aggressive lowering should be avoided in the acute phase.
  • Supportive Care: Ensure adequate oxygenation, monitor for complications (such as cerebral edema or seizures), and provide supportive care to maintain systemic homeostasis.

3. Rehabilitation:

  • Physical Therapy: To improve motor function and mobility.
  • Occupational Therapy: To assist with activities of daily living.
  • Speech Therapy: To address speech and swallowing difficulties.
  • Multidisciplinary Care: A coordinated approach involving neurologists, physiatrists, nurses, and other healthcare professionals.

Role of Mesenchymal Stem Cells (MSC) in Improving Stroke Outcome

1. Mechanism of Action:

  • Neuroprotection: MSCs secrete neurotrophic factors that can protect neurons from ischemic damage.
  • Angiogenesis: Promote the formation of new blood vessels, enhancing blood flow to the affected brain areas.
  • Anti-inflammatory Effects: Reduce inflammation and modulate the immune response, which can limit secondary injury.
  • Neurogenesis: Encourage the growth of new neurons and repair damaged neural networks.
  • Cell Replacement: Although limited, MSCs can differentiate into neuronal and glial cells, potentially replacing lost cells.

2. Timing of MSC Administration:

  • Acute Phase: Administration within the first hours to days post-stroke can be crucial for neuroprotection and reducing acute inflammatory responses. Studies suggest that early intervention may lead to better outcomes.
  • Subacute Phase: Administration during the subacute phase (days to weeks post-stroke) can still be beneficial, primarily through promoting repair and reducing secondary damage.
  • Chronic Phase: MSC therapy can also be considered in the chronic phase (weeks to months post-stroke) to enhance neurogenesis and functional recovery, although the outcomes might be less pronounced compared to earlier administration.

3. Methods of Administration:

  • Intravenous Injection: The most common method due to its simplicity, though the efficiency of cell delivery to the brain might be limited.
  • Intra-arterial Injection: Direct delivery to the cerebral circulation can enhance the targeting of the affected brain areas.
  • Intrathecal Injection: Delivery into the cerebrospinal fluid for closer proximity to the brain tissue.
  • Direct Intracerebral Injection: Invasive, but ensures direct delivery of cells to the infarcted area.

Clinical Evidence

1. Preclinical Studies:

Preclinical studies in animal models have shown promising results for MSC therapy in ischemic stroke. These studies have demonstrated that MSCs can significantly reduce the infarct size and improve neurological function. For example, in rodent models, MSCs have been shown to enhance neurogenesis, promote angiogenesis, and reduce inflammation in the ischemic brain .

2. Early-Phase Clinical Trials:

  • PISCES Trial: The Pilot Investigation of Stem Cells in Stroke (PISCES) trial was one of the first human trials to assess the safety of neural stem cells in patients with chronic ischemic stroke. The study demonstrated that MSC therapy was well tolerated, with no serious adverse events related to the stem cell treatment. Some patients showed modest improvements in neurological function .
  • MASTERS Trial: The Multistem Administration for Stroke Treatment and Enhanced Recovery Study (MASTERS) was a phase 2 trial investigating the safety and efficacy of multipotent adult progenitor cells (a type of MSC) in acute ischemic stroke patients. Results showed that the treatment was safe and feasible, with some evidence of improved functional outcomes compared to the placebo group .

3. Randomized Controlled Trials:

Larger randomized controlled trials are ongoing to establish the efficacy and optimal protocols for MSC therapy in ischemic stroke. These trials aim to determine the best timing, dosage, and delivery method for MSCs to maximize patient outcomes.

4. Meta-Analyses and Systematic Reviews:

Meta-analyses and systematic reviews of existing studies have indicated that MSC therapy has the potential to improve functional outcomes in stroke patients. These reviews highlight the need for further large-scale, high-quality trials to confirm the benefits and establish standardized treatment protocols .

Conclusion

The management of ischemic stroke involves acute intervention, supportive care, and rehabilitation. MSCs offer a promising adjunctive therapy, potentially improving outcomes through multiple mechanisms. The timing of MSC administration is critical, with early intervention likely providing the greatest benefit. As research progresses, MSC therapy may become a standard part of stroke management, offering hope for enhanced recovery and better quality of life for stroke survivors.

References

  1. Borlongan CV, Glover LE, Tajiri N, et al. The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Prog Neurobiol. 2011;95(2):213-228.
  2. Wang Y, Deng Y, Zhou GQ. SDF-1α/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesions in a rat model. Brain Res. 2008;1195:104-112.
  3. Kalladka D, Sinden J, Pollock K, et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet. 2016;388(10039):787-796.
  4. Hess DC, Wechsler LR, Clark WM, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017;16(5):360-368.
  5. Vu Q, Xie K, Eckert M, et al. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82(14):1277-1286.
  6. Bang OY, Lee JS, Lee PH, et al. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874-882.