Stem cell therapy modulates inflammasome signaling in stroke: Possible involvement of Mitochondria? (1588)

Objective: Our aim is to explore whether intra-arterial (IA) MSCs can inhibit production of NLRP1 by mitigating ASIC1a expression to render neuroprotection and further to explore if it influences mitochondria transfer from stem cells to hypoxic neuronal cells. Background: Stroke is the second leading cause of death and disability worldwide. Acidosis following ischemia, worsens the pathology by activating the acid sensing ion channel 1a (ASIC1a). This activated ASIC1a increases the expression of NLRP1 inflammasome in a pH dependent manner that further activates the inflammatory cascade. ASIC1a then triggers the influx of Ca 2+ ions, overload of which contributes to neuronal injury in ischemic stroke. Inflammasome causes mitochondrial dysfunction and also modulates mitochondrial transfer. Cell based therapy with mesenchymal stem cells (MSCs) is a promising approach for clinical translation and reported to act on inflammasomes and mitochondrial dysfunction. Design/Methods: Ovariectomized Sprague Dawley rats were infused with IA MSCs at 6 hours post middle cerebral artery occlusion (MCAo) followed by 24 hours of reperfusion. Rats were evaluated for motor functions and neurodeficits. Brains were harvested for infarct size estimation, biochemical analysis and western blot experiments. Results: IA MSCs when given at a dose of 1x10 5 cells at 6 hours following ischemia confers neuroprotection as evident by the reduction in infarct volume, improvement in motor function and neurodeficits. An increase in GSH levels and concomitant reduction in elevated nitrite and MDA levels were observed in the IA MSCs treated animals. Expression of ASIC1a, NLRP1, NLRP3, ASC1, IL1β and caspase-1 were reduced following IA MSCs infusion in the cortical brain regions following ischemia Further, our preliminary in vitro studies have revealed transfer of mitochondria from stem cells to hypoxic neuronal cells and has involvement of inflammasome signaling in this process. Conclusions: IA MSCs modulate ASIC1a mediated NLRP1 expression and influence mitochondrial transfer to confer neuroprotection in ischemic stroke. Disclosure: Dr. Bhattacharya has nothing to disclose. Dr. Sarmah has nothing to disclose. Dr. Datta has nothing to disclose. Dr. Kaur has nothing to disclose. Dr. Kalia has nothing to disclose. Dr. Yavagal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Medtronic, GLG, Guidepoint. Dr. Yavagal has received research support from Medtronic.