Stem Cells Run Like Clockwork for Stroke Therapeutics

Abstract

Accumulating evidence reveals an association between stroke and circadian rhythm, but whether circadian rhythm manifests in stem cells remains underexplored. Here, we examined the presence of circadian rhythm in stem cells in both ambient and stroke conditions. Under ambient culture conditions, umbilical cord-derived mesenchymal stem cells (UC-MSCs) exhibited a cycle of 10–15 h with a slight frameshift between cell mobilization and proliferation. BMAL1 and PER2 clock gene expressions matched cell mobilization rhythms. The proliferative marker c-Fos expression directly mirrored cell proliferation, but inversely reflected cell mobilization and clock genes, whereas the cytoskeletal marker F-actin expression displayed an oscillation pattern independent of stem cell activity rhythms and clock genes. Under oxygen-glucose deprivation (OGD) conditions, UC-MSCs with high levels of BMAL1/PER2 (HBP) significantly improved survival and viability of OGD-exposed human neural progenitor cells (hNPCs) compared to moderate levels (MBP) and low levels (LBP) of BMAL1/PER2, with clock gene expressions mirroring the therapeutic effects of HBP UC-MSCs. During this acute time-point post-OGD when HBP UC-MSCs rescued hNPCs from OGD, F-actin expression robustly increased while c-Fos expression moderately upregulated, implicating a more active cytoskeletal remodeling than cell proliferation towards cell repair. These results suggest that optimizing the timing of stem cell activity (i.e., high levels of BMAL1/PER2) enhances stem cell therapy for stroke.