Endovascular Stem Cell Therapy Post Stroke Rescues Neurons from Endoplasmic Reticulum Stress-Induced Apoptosis by Modulating Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling.

Abstract

Ischemic stroke is devastating, with serious long-term disabilities affecting millions of people worldwide. Growing evidence has shown that mesenchymal stem cells (MSCs) administration after stroke provides neuroprotection and enhances the quality of life in stroke patients. Previous studies from our lab have shown that 1 × 105 MSCs administered intra-arterially (IA) at 6 h post stroke provide neuroprotection through the modulation of inflammasome and calcineurin signaling. Ischemic stroke induces endoplasmic reticulum (ER) stress, which exacerbates the pathology. The current study intends to understand the involvement of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling in preventing apoptosis induced by ER stress post stroke following IA MSCs administration. Ischemic stroke was induced in ovariectomized female Sprague Dawley rats. The MSCs were administered IA, and animals were sacrificed at 24 h post stroke. Infarct area, neurological deficit score, motor coordination, and biochemical parameters were evaluated. The expression of various genes and proteins was assessed. An inhibition study was also carried out to confirm the involvement of BDNF/TrkB signaling in ER stress-induced apoptosis. IA-administered MSCs improved functional outcomes, reduced infarct area, increased neuronal survival, and normalized biochemical parameters. mRNA and protein expression of ER stress markers were reduced, while those of BDNF and TrkB were increased. Reduction in ER stress-mediated apoptosis was also observed. The present study shows that IA MSCs administration post stroke provides neuroprotection and can modulate ER stress-mediated apoptosis via the BDNF/TrkB signaling pathway.