Abstract
Abstract only Background: Neurodevelopmental impairment is one the most important challenges in children with congenital heart disease. Cardiopulmonary bypass (CPB) causes substantial oxidative/inflammatory stress and microglial activation. The present study tested CPB itself as a unique delivery system of bone marrow-derived mesenchymal stromal cells (BM-MSCs), known to possess significant immunomodulatory properties. Methods: Two-week old piglets were randomly assigned to one of three groups: Control, CPB, and CPB with BM-MSC administration. BM-MSCs (10x10 6 /kg) were delivered through CPB. In addition to cellular/molecular assays, structural and behavioral changes were assessed up to 4 weeks after surgery. Results: Intra-arterial delivery through CPB uniformly distributed BM-MSCs to most of the organs analyzed, including the brain, heart and kidney. In the brain, BM-MSCs were equally distributed between two hemispheres and within the cortex and white matter. While approximately half of the BM-MSCs were localized to parenchyma shortly after CPB, there were no residual MSCs at 4 weeks post-CPB. In the developing cortex, enhanced p53 and JAK-STAT3 pathway activation were revealed post-CPB. BM-MSCs suppressed CPB-induced microglial STAT3 phosphorylation, thereby inhibiting microglial activation. In addition to an increase in anti-inflammatory cytokines, BM-MSCs reduced caspase-3 activation in cortical neurons and limited the induction of apoptotic signals. BM-MSC-treated animals demonstrated improved post-operative recovery and reduced behavioral impairments due to cardiac surgery. Concurrently, CPB-induced structural alterations of the developing cortex were mitigated possibly through the inhibition of prolonged microglia activation by BM-MSCs. No evidence of any detrimental effects was observed. Our transcriptomic analyses suggest that BM-MSC exosome-derived micro-RNA, miR-21-5p, may be the key mediator of apoptosis suppression and reduced microglial activation. Conclusions: BM-MSC delivery via CPB minimizes inflammatory/oxidative stress and reduces neuronal caspase and microglial activation, with subsequent rescue of behavioral/structural impairments in children undergoing cardiac surgery.