Mesenchymal Stem Cell-Derived Mitochondria Enhance Extracellular Matrix-Derived Grafts for The Repair of Nerve Defect.

Peripheral nerve injuries (PNI) can lead to mitochondrial dysfunction and energy depletion within the affected microenvironment. Our objective was to investigate the potential of transplanting mitochondria to reshape the neural regeneration microenvironment. High-purity functional mitochondria with an intact structure were extracted from human umbilical cord-derived mesenchymal stem cells (hUCMSCs) using the Dounce homogenization combined with ultracentrifugation. Results showed that when hUCMSC-derived mitochondria (hUCMSC-Mitos) were co-cultured with Schwann cells (SCs), they promoted the proliferation, migration, and respiratory capacity of SCs. Acellular nerve allografts (ANAs) have shown promise in nerve regeneration, however, their therapeutic effect is not satisfactory enough. The incorporation of hUCMSC-Mitos within ANAs (referred to as Mito-ANAs) has the potential to remodel the regenerative microenvironment. This approach demonstrated satisfactory outcomes in terms of tissue regeneration and functional recovery. Particularly, we propose for the first time the use of metabolomics and bioenergetic profiling to analyze the energy metabolism microenvironment after PNI. This remodeling occurs through the enhancement of the tricarboxylic acid (TCA) cycle and the regulation of associated metabolites, resulting in increased energy synthesis. Overall, the hUCMSC-Mito-loaded ANAs exhibited high functionality to promote nerve regeneration, providing a novel regenerative strategy based on improving energy metabolism for neural repair. This article is protected by copyright. All rights reserved.