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.

Yongjin Sun,Xiaoxu Yang,Bi Chen,Wenzhi Zhang,Xu Li,Tullia Maraldi

doi:10.1155/2021/9955448

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.

Highlights

Intervertebral disc degeneration (IVDD) is widely thought to contribute to a series of painful spinal disorders and poses a major global health threat [1]
Our results showed that Adipo-small extracellular vesicles (sEVs) could deliver nicotinamide phosphoribosyltransferase (NAMPT) to senescent nucleus pulposus (NP) cells (NPCs) and EP cells (EPCs) and enhance NAD+ biosynthesis in cells
Given that Adipo-sEV-contained NAMPT is crucial in the Adipo-sEV-mediated rejuvenation of senescent NPCs, we explored whether this mechanism could explain the effects of Adipo-sEVs on rejuvenating senescent EPCs

Summary

Introduction

Intervertebral disc degeneration (IVDD) is widely thought to contribute to a series of painful spinal disorders and poses a major global health threat [1]. AF and NP allow the disc to manage diverse external mechanical stresses, while EP is crucial for the inner NP nutrient supply. Accumulating evidence indicates that the senescence of NP cells (NPCs) and EP cells (EPCs) plays a pivotal role in the development of IVDD [3, 4]. Oxidative stress in IVD may be caused by external overload drive cells to exhibit aging-associated phenotypes [5, 6]. This leads to blockage of the nutrition channel in EP and disrupts the balance of nutrients and metabolites entering and exiting the disc, which further accelerates the degeneration of NPCs [8, 9].

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