Mesenchymal Stem Cell‐Derived Mitochondria Enhance Extracellular Matrix‐Derived Grafts for the Repair of Nerve Defect

Abstract

Peripheral nerve injuries (PNI) can lead to mitochondrial dysfunction and energy depletion within the affected microenvironment. The objective is to investigate the potential of transplanting mitochondria to reshape the neural regeneration microenvironment. High‐purity functional mitochondria with an intact structure are extracted from human umbilical cord‐derived mesenchymal stem cells (hUCMSCs) using the Dounce homogenization combined with ultracentrifugation. Results show that when hUCMSC‐derived mitochondria (hUCMSC‐Mitos) are cocultured with Schwann cells (SCs), they promote 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 has the potential to remodel the regenerative microenvironment. This approach demonstrates satisfactory outcomes in terms of tissue regeneration and functional recovery. Particularly, the use of metabolomics and bioenergetic profiling is used for the first time to analyze the energy metabolism microenvironment after PNI. This remodeling occurs through the enhancement of the tricarboxylic acid cycle and the regulation of associated metabolites, resulting in increased energy synthesis. Overall, the hUCMSC‐Mito‐loaded ANAs exhibit high functionality to promote nerve regeneration, providing a novel regenerative strategy based on improving energy metabolism for neural repair.

MSC-derived mitochondria promote axonal regeneration via Atf3 gene up-regulation by ROS induced DNA double strand breaks at transcription initiation region

“…For the mechanism of mitochondrial treatment, it is possible that mitochondria can be taken up by Schwann cells (SCs) and promote their supportive function in nerve injury repair, indirectly facilitating axonal regeneration. Bai et al have demonstrated that grafts enriched with MSCderived mitochondria effectively treated sciatic nerve defects, confirming the uptake of mitochondria by SCs, which promotes proliferation and migration through enhanced energy synthesis, ultimately leading to axonal regeneration [68]. It will be intreseting to investigate the phenomenon and function of mitochondrial uptake in SCs following the mitochodrial injection therapy in SNI models.…”

Engineering cell-derived extracellular matrix for peripheral nerve regeneration

“…In the field of peripheral nerve tissue engineering, acellular allogeneic nerves are typical td-ECM scaffolds. They preserve the native heterogeneous composition and inherent ultrastructure, therefore possessing tissue-specific functionality to some extent [ 24 , 25 ]. Acellular nerve grafts have been widely selected in the treatment of PNI and there are commercially available finished products that have been approved [ 26 , 27 ].…”