Abstract
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-β-galactosidase activity and the expression of the senescence-associated factor p16INK4a. 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.
Highlights
Adult stem cells (SCs), which reside in various tissues and organs, are critical for homeostasis maintenance and tissue regeneration
Senescence-associated alterations in mesenchymal SCs (MSCs) at late passage are associated with reduced nicotinamide phosphoribosyltransferase (Nampt) expression and attenuated NAD+-Sirt1 signaling
There is abundant evidence that Nampt is closely related to cellular senescence in somatic cells
Summary
Adult stem cells (SCs), which reside in various tissues and organs, are critical for homeostasis maintenance and tissue regeneration. Regardless of the donor’s age, MSCs cultured in vitro will inevitably senesce with an increasing number of passages, and this has adverse effects on the amplification and functionality of cells. This contributes to the paucity of seeding cells for SC-based therapies and severely restricts their application in basic scientific research, tissue repair, autotransplantation, and the treatment of clinical diseases. The molecular mechanisms underlying MSC replicative senescence are still not fully elucidated
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