Mesenchymal Stem Cell‐Derived Apoptotic Micro‐Vesicles Repaired Sciatic Nerve Defect by Regulating Early Inflammatory Microenvironment and Promoting Angiogenesis

The early imbalance in the inflammatory microenvironment (IME) following peripheral nerve injury (PNI) poses a major impediment to nerve regeneration. This study elucidates the mechanism through which human umbilical cord mesenchymal stem cell-derived apoptotic microvesicles (HUCMSC-Apo-mvs) facilitate peripheral nerve repair via IME modulation. Comparative proteomics and miRNA sequencing analyses are conducted to identify compositional differences between exosomes (Exos) and Apoptotic microvesicles (Apo-mvs) originating from the same parental HUCMSC. Early administration of HUCMSC-Apo-mvs at the transection injury site induced substantial macrophage recruitment. Contrary to Exos, Apo-mvs significantly inhibited pro-inflammatory M1-type macrophage polarization while promoting their transition to the anti-inflammatory M2-type phenotype. This shift is accompanied by an enhanced secretion of anti-inflammatory cytokines [Interleukin 10 (IL-10) and vascular endothelial growth factor (VEGF)], improved local angiogenesis, and the consequent alleviation of tissue hypoxia and neuroinflammation. Both Apo-mvs and Exos enhanced Schwann cell (SC) migration and proliferation, thereby accelerating axonal regeneration and myelin remodeling. Animal studies further revealed that HUCMSC-Apo-mvs markedly improved early-stage sciatic nerve regeneration, with long-term functional recovery comparable to autologous nerve grafts. To the best of our knowledge, this is the first study to demonstrate the differential components between mesenchymal stem cell (MSC)-derived Exos and Apo-mvs, as well as their potential novel application in combination with acellular allogeneic nerve grafts for early inflammatory regulation in PNI. We hope that our findings will provide an experimental basis for the clinical translation of cell-free tissue engineering approaches in MSC-mediated peripheral nerve regeneration.