Small Extracellular Vesicles Derived from Adipocytes Attenuate Intervertebral Disc Degeneration in Rats by Rejuvenating Senescent Nucleus Pulposus Cells and Endplate Cells by Delivering Exogenous NAMPT

Abstract

Cellular senescence is a key factor in the development of intervertebral disc degeneration (IVDD). Age-associated decreases in NAD+ levels play a critical role in regulating cellular senescence. Previous studies have found that small extracellular vesicles (sEVs) secreted by adipocytes (Adipo-sEVs) or adipose tissue are abundant in nicotinamide phosphoribosyltransferase (NAMPT), which is the key NAD+ biosynthetic enzyme in mammals. Systemic injection of these sEVs significantly improves physical activity and extends the lifespan of aged mice by increasing NAD+ levels. However, to date, the therapeutic potential of Adipo-sEVs in other age-associated disease models, such as IVDD, has not been explored. In this study, we investigated the therapeutic effects of Adipo-sEVs on senescence of nucleus pulposus cells (NPCs) and cartilaginous endplate cells (EPCs). In vitro, Adipo-sEVs could rejuvenate the senescence of NPCs and EPCs. Age-related dysfunctions were also ameliorated by Adipo-sEVs by delivering NAMPT and activating NAD+ biosynthesis and the Sirt1 pathway. Further in vivo experiments revealed that Adipo-sEV-mediated delivery of NAMPT attenuated IVDD in rats by rejuvenating senescent NPCs and EPCs. Collectively, the results indicate a new cell-free tool and provide a promising sEV-mediated delivery method of NAMPT as a therapeutic approach for IVDD clinically.