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Modified MSCs enhance functional recovery and neuroplasticity in chronic stroke via mechanisms involving angiogenesis, neurogenesis and anti-fibrosis

Authors
Subash Marasini; Yoo, Seung-Wan; Chang, Da Young; Lee, Young-Don
Department
Department of Anatomy
Abstract
Stroke is a dominant cause of sensorimotor disability. Due to a limited or partial spontaneous functional recovery, stroke survivors often suffer from sensory-motor dysfunctions and various degrees of paralysis for several subsequent years. We previously reported that in acute phase of stroke, mesenchymal stem cells ameliorated stroke damage via several ways involving immunomodulation and neuroprotection. In this study, we found that MSCs were unable to exert similar beneficial effect when transplanted in the chronic phase. This inability of MSCs in the treatment of chronic stroke could be attributed to the presence of unfavorable tissue environment. We genetically modified MSCs using adenovirus encoding several genes and transplanted in chronic stroke brain. Treatment with genetically modified MSCs significantly improved the behavioral and histological deficits when assessed with sensory-motor function tests and MRI respectively. Immunohistochemical analyses indicated that transplantation of those genetically modified stem cells rejuvenated the microenvironment of the damaged brain tissue and activated the quiescent endogenous neural stem cells in a transgenic mouse model where neural stem/progenitor cells can be detected as EGFP. We also obtained similar results in vitro studies indicating those cells exerted proangiogenic effects. Our genetically modified MSCs, satisfied the STEP3 guidelines suggested for preclinical studies by FDA and NIH (2014), might provide a potential therapeutic strategy for the treatment of chronic stroke.
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