Hydrogen Sulfide Attenuates Mesenchymal Stem Cell Aging Progress via the Calcineurin-NFAT Signaling Pathway

Abstract Aging is a gradual process that is coupled with a decline in the regenerative capacity of stem cells and a subsequent reduction in tissue function and repair. Hydrogen sulfide (H2S) plays an important role in maintaining the function of stem cells. The present study aimed to investigate the role of H2S in mesenchymal stem cell aging and the underlying mechanism and to provide novel insights into stem cell therapies in elderly people. Bone marrow mesenchymal stem cells (BMMSCs) were isolated from young mice (2 months) and from old mice (12 months). Senescence-associated β-galactosidase (SA-β-Gal) activity, reactive oxygen species (ROS) production, ROS scavenging enzymes, and the expression of cell-cycle-related genes were compared between those young and old BMMSCs. The expression of H2S-producing enzymes and the production of H2S in BMMSCs were examined. In vitro osteogenic differentiation and cell senescence were analyzed in young and old BMMSCs before and after H2S treatment. The underlying mechanism was investigated using calcineurin and NFAT1 inhibitors or a Foxp3 siRNA. Bone volume/tissue volume (BV/TV) of femurs in mice was examined using micro-CT with or without systemic injection of an H2S donor. Here, we found that H2S levels in BMMSCs declined with age. When the generation of H2S was blocked with the CBS inhibitor hydroxylamine and the CSE inhibitor dl-propargylglycine, BMMSCs underwent senescence. The elevation of H2S levels rescued BMMSC function in vitro and prevented bone loss in vivo. Mechanistically, H2S represses cell aging via the calcineurin-NFAT1 signaling pathway.