SIRT-1/RHOT-1/PGC-1α loop modulates mitochondrial biogenesis and transfer to offer resilience following endovascular stem cell therapy in ischemic stroke

Abstract

Current clinical interventions for stroke majorly involve thrombolysis or thrombectomy, however, cessation of the progressive deleterious cellular cascades post-stroke and long-term neuroprotection are yet to be explored. Mitochondria are highly vulnerable organelles and their dysfunction is one of the detrimental consequences following stroke. Mitochondria dysregulation activate unfavourable cellular events over a period of time that leads to the collapse of neuronal machinery in the brain. Hence, strategies to protect and replenish mitochondria in injured neurons may be useful and needs to be explored. Stem cell therapy in ischemic stroke holds a great promise. Past studies have shown beneficial outcomes of endovascularly delivered stem cells in both pre-clinical and clinical settings. Intra-arterial (IA) administration can provide more cells to the stroke foci and affected brain regions than intravenous administration. Supplying new mitochondria to the stroke-compromised neurons either in the core or penumbra by infused stem cells can help increase their survival and longevity. Previously, our lab has demonstrated that IA 1∗10⁵ mesenchymal stem cells (MSCs) in rats were safe, efficacious and rendered neuroprotection by regulating neuronal calcineurin, modulating sirtuin1(SIRT-1) mediated inflammasome signaling, ameliorating endoplasmic reticulum-stress, alleviation of post-stroke edema and reducing cellular apoptosis. To explore further, our present study aims to investigate the potential of IA MSCs in protecting and replenishing mitochondria in the injured neurons post-stroke and the involvement of SIRT-1/RHOT-1/PGC-1α loop towards mitochondria transfer, biogenesis, and neuroprotection. This study will open new avenues for using stem cells for ischemic stroke in clinics as one of the future adjunctive therapies.