Nicotinamide phosphoribosyltransferase postpones rat bone marrow mesenchymal stem cell senescence by mediating NAD+-Sirt1 signaling

In vitro replicative senescence affects MSC characteristics and functionality, thus severely restricting their application in regenerative medicine and MSC-based therapies. Previously, we found that MSC natural senescence is accompanied by altered intracellular nicotinamide adenine dinucleotide (NAD(+)) metabolism, in which Nampt plays a key role. However, whether Nampt influences MSC replicative senescence is still unclear. Our study showed that Nampt expression is down-regulated during MSC replicative senescence. Nampt depletion via a specific Nampt inhibitor FK866 or Nampt knockdown in early passage MSCs led to enhanced senescence as indicated by senescence-like morphology, reduced proliferation, and adipogenic and osteogenic differentiation, and increased senescence-associated-beta-galactosidase activity and the expression of the senescence-associated factor p16(INK4a). Conversely, Nampt overexpression ameliorated senescence-associated phenotypic features in late passage MSCs. Further, Nampt inhibition resulted in reduced intracellular NAD(+) content, NAD(+)/NADH ratio, and Sirt1 activity, whereas overexpression had the opposite effects. Exogenous intermediates involved in NAD(+) biosynthesis not only rescued replicative senescent MSCs but also alleviated FK866-induced MSC senescence. Thus, Nampt suppresses MSC senescence via mediating NAD(+)-Sirt1 signaling. This study provides novel mechanistic insights into MSC replicative senescence and a promising strategy for the severe shortage of cells for MSC-based therapies.