Molecular Pathophysiology of Ischemic Stroke and Mesenchymal Stem Cell Based Therapeutic Strategies for Neural Tissue Regeneration: A Pre-clinical and Clinical Perspective.

Ischemic stroke (IS), also referred to as cerebral ischemia, is a neurological condition accompanied by long term or permanent physical disability. Various molecular mechanisms such as inflammation, oxidative stress, blood brain barrier (BBB) disruption, energy depletion, mitochondrial dysfunction etc., contribute to its pathophysiology and trigger death of neural tissues. Currently, there are limited therapeutic options for its treatment. Although, thrombectomy or thrombolytic drugs are available, but only beneficial for the management of acute phase and do not address the neurodegenerative aspects. Mesenchymal stem cells (MSCs) are predominantly used for regenerative applications due to their self-renewal, immunomodulatory, and neuronal differentiation potential which make them a suitable candidate for neural tissue regeneration at both pre-clinical and clinical levels. MSC derived exosomes and extracellular vesicles (EVs) also provide cell-free therapeutic option that potentially reduce inflammation, restore BBB integrity, and facilitate neural regeneration. The current review summarizes the molecular mechanisms associated with IS pathophysiology and therapeutic mechanisms exhibited by MSCs and their derived products. Furthermore, the review also highlights the clinical trials registered so far to examine the efficacy of MSCs and their derived products to validate the findings and address challenges associated with preclinical studies. A number of clinical trials have reported improvements in motor functions and neurological scores, demonstrating MSC based therapy as safe and effective to treat IS complications. However, there is still a need to fully optimize protocols for MSC source, delivery route, dose, and timing of administration to maximize therapeutic efficacy and ensure safety in future clinical applications.