200 Section - Source-Dependent Mitochondrial Transplantation Drives Schwann Cell Bioenergetic Reprogramming and Peripheral Nerve Regeneration

Objectives : Clinical recovery after peripheral nerve injury (PNI) is often poor, partly due to impaired energy metabolism in the regenerative microenvironment. Schwann cell (SC) metabolic reprogramming is critical for axonal regeneration. Mitochondrial transplantation (MT) has been proposed as a therapeutic strategy, but its effects beyond transient energy supplementation remain unclear.

Design: Mitochondria from human induced pluripotent stem cells (iPSCs) and induced mesenchymal stem cells (iMSCs) were characterized by LC/MS metabolomics. Their effects on SC energy metabolism, proliferation, migration, and neurotrophic factor expression were evaluated in vitro, including in H₂O₂-induced oxidative injury and glycolysis inhibition assays. In vivo, a 10 mm sciatic nerve transection model in rats received local MT, and sensory/motor recovery, axonal regeneration, myelination, and target muscle function were assessed over 12 weeks. RNA-Seq was used to explore underlying mechanisms.

Results: iPSCs and iMSCs displayed distinct metabolic profiles, with iMSCs showing stronger glycolysis and oxidative phosphorylation and higher mitochondrial membrane potential. SCs efficiently internalized both mitochondria types, resulting in increased ATP production, membrane potential, proliferation, migration, and neurotrophic factor expression. MT reduced ROS levels and apoptosis under oxidative stress, with iMSC-derived mitochondria mainly enhancing glycolysis to reprogram SC metabolism. In a rat sciatic nerve injury model, MT markedly improved axonal regeneration, remyelination, and sensory and motor functional recovery. Notably, iMSC-derived mitochondria exhibited superior metabolic adaptability and therapeutic efficacy.

Conclusion: Collectively, our findings demonstrate that iMSC-derived mitochondria promote nerve repair by driving metabolic reprogramming rather than merely providing transient bioenergetic support, thereby offering a mechanistic framework for optimizing mitochondrial donor selection in regenerative therapies.