Endovascular stem cell therapy reconfigures post-stroke ER dynamics via GRP78/Atlastin/CHOP axis

The endoplasmic reticulum (ER) resident chaperon proteins require calcium for post-translational modifications and maintaining ER integrity. Post-stroke dysregulation of ER associated calcium homeostasis leads to altered ER dynamics and neurodegeneration. Previously, we have observed that post-stroke intra-arterial mesenchymal stem cells (IA-MSCs) administration renders neuroprotection and alleviates ER stress. Subsequently, the current study aims to investigate the role of IA-MSCs in modulating the post-stroke calcium homeostasis towards regulating ER dynamics. Male SD rats were administered with 1*10⁵ IA-MSCs at 6 h following ischemic stroke. Behaviour and motor impairment were evaluated at day 1, 7, and 14. Biochemical, histopathological, protein, and gene expression studies were also performed using cortical brain tissues. IA-MSCs administration following ischemic injury led to reduced infarct size, oxidative stress, and improved functional outcomes. It also modulated the protein and gene expressions of atlastin, reticulon, climp63 responsible for changes in the ER morphology and dynamics as evident from molecular and histological studies. Additionally, a significant decrease in the level of GRP78 and calreticulin following IA-MSCs administration, suggesting the role of IA-MSCs in maintaining calcium homeostasis. Further, we have observed that IA-MSCs administration alleviated the ER-stress induced apoptosis as evident from the reduced gene and protein expression of CHOP. Thus, the study emphasizes the therapeutic potential of IA-MSCs in ischemic stroke towards regulating the calcium-mediated ER dynamics with its future possibility as one of the adjunctive therapies for ischemic stroke.