MSC-derived exosomes alleviate oxidative stress-induced lysosomal membrane permeabilization damage in degenerated nucleus pulposus cells via promoting m6A demethylation of Nrf2

This is the authors' abstract. We don't add key points for this paper.

Lysosomal membrane permeabilization (LMP) is a specific feature of lysosomal dysfunction; however, its specific role and underlying mechanisms involved in intervertebral disc degeneration (IVDD) remain elusive. Although the therapeutic potential of mesenchymal stem cell-derived exosomes (MSC-Exo) in ameliorating IVDD has been verified, it remains unclear whether their protective effects are referred to LMP damage. This work revealed that oxidative stress induced-LMP damage directly mediated the pathological process of human IVDD, which aggravated nucleus pulposus cells (NPCs) senescence by disrupting lysosomal autophagy function. Conversely, umbilical cord derived MSC-Exo inhibited LMP damage in degenerated NPCs by activating Nrf2-medaited anti-oxidative stress effects. Specifically, MSC-Exo facilitated H3K27ac modification in the demethylase FTO promoter by promoting histone acetyltransferase activity of p300/CBP, resulting in the enhanced FTO transcription. This process inhibited the elevation of N6-methyladenosine (m6A) modification of Nrf2 in degenerated NPCs, resulting in less recognition of YTHDF2 and enhanced stability of Nrf2 expression. Here, our finding demonstrates oxidative stress induced-LMP damage potentially establishing pathological conditions conducive to the progression of IVDD, and providing epigenetic regulatory targets for MSC-Exo in the treatment of IVDD.