Human iPSCs Derived MSCs‐Secreted Exosomes Modulate Senescent Nucleus Pulposus Cells Induced Macrophage Polarization via Metabolic Reprogramming to Mitigate Intervertebral Disc Degeneration

Abstract Intervertebral disc degeneration (IDD) is a leading cause of discogenic lower back pain, yet the crosstalk between macrophage polarization and nucleus pulposus (NP) cell senescence in IDD progression remains poorly understood. Emerging therapies using human induced pluripotent stem cell (iPSCs)‐derived mesenchymal stem cells (iMSCs) show promise for IDD treatment. In this study, it is first demonstrated that senescent NP cells promote macrophage polarization toward the pro‐inflammatory M1 phenotype in coculture systems. Reciprocally, conditioned medium from M1 macrophages exposed to senescent NP cells accelerates senescence in healthy NP cells. Notably, it is identified that iMSCs‐derived exosomes break this pathogenic cycle by reprogramming M1 macrophages toward anti‐inflammatory M2 phenotypes. Mechanistically, these exosomes deliver miR‐100‐5p to suppress mTORC1 signaling and regulate glycolysis metabolic reprogramming in macrophages. These findings are corroborated in a rat IDD model, where iMSC‐exosomes mitigate IDD progression in vivo. This work elucidates a novel iMSC‐exosomes mediated mechanism regulating macrophage‐NP cell interactions, which provides a promising therapeutic strategy for IDD intervention.