# Apoptotic extracellular vesicles derived from MSCs exposed to hypoxic and inflammatory environments slow intervertebral disc degeneration by enhancing cell activity and regulating immunity microenvironment

## TL;DR

This study shows that extracellular vesicles from stem cells, treated with a hypoxic and inflammatory environment, can slow disc degeneration by boosting cell activity and reducing inflammation.

## Contribution

The novel approach uses hypoxia and inflammation-pretreated stem cell-derived apoptotic vesicles to target IVDD.

## Key findings

- I-ApoEVs significantly inhibited NPCs senescence and promoted ECM synthesis.
- I-ApoEVs regulated the STAT6 pathway and induced M2 macrophage polarization.
- The treatment alleviated inflammation-mediated degenerative damage in intervertebral discs.

## Abstract

Intervertebral disc degeneration (IVDD) is characterized by the senescence and apoptosis of nucleus pulposus cells (NPCs), metabolic imbalance of the extracellular matrix (ECM), and local chronic inflammation, presenting a long-standing challenge in clinical treatment. Recent studies have confirmed that transplanted stem cells are prone to apoptosis in vivo, and the apoptotic extracellular vesicles (ApoEVs) they produce are key mediators of tissue repair. Given that both the physiological state of mesenchymal stem cells (MSCs) and the IVDD microenvironment exhibit hypoxic and inflammatory features, this study investigated the therapeutic effect and mechanism of MSCs-derived apoptotic bodies (I-ApoEVs) pretreated with a hypoxic-inflammatory composite microenvironment on IVDD. The results showed that compared with ApoEVs under conventional hypoxic conditions, I-ApoEVs more significantly inhibited NPCs senescence and promoted ECM synthesis. More importantly, they could target and regulate the STAT6 signaling pathway, induce macrophages to polarize towards the M2 anti-inflammatory phenotype, thereby remodeling the local inflammatory microenvironment of the intervertebral disc and alleviating inflammation-mediated degenerative damage. In conclusion, pretreatment with a hypoxic-inflammatory composite microenvironment enhances the therapeutic function of ApoEVs by regulating macrophage polarization, providing a novel and highly translatable therapeutic strategy for IVDD.

An overview of the study design is shown in Scheme 1.Scheme 1. Schematic diagram of apoptotic extracellular vesicles (ApoEVs) in relieving intervertebral disc degeneration. ApoEVs derived from hypoxic and inflammatory composite microenvironment preconditioned rat bone mesenchymal stem cells (BMSCs) enhance nucleus pulposus cells (NPCs) activity and regulate immunity to promote intervertebral disc (IVD) repair.Image 1