Therapeutic potential of human mesenchymal stromal cell-derived mitochondria in a rat model of surgical digestive fistula

Mitochondria are central to cellular energy metabolism and play a critical role in tissue regeneration. Mitochondrial dysfunction contributes to a range of degenerative conditions and impaired wound healing, driving increasing interest in mitochondrial transplantation as a novel therapeutic strategy. Gastrointestinal wound healing is particularly susceptible to failure, with complications such as post-surgical fistula formation commonly occurring after procedures like sleeve gastrectomy. Mitochondria derived from human mesenchymal stromal/stem cells (hMSCs) have shown promise in restoring tissue bioenergetics and promoting repair across various disease models. In this study, we evaluated the therapeutic potential of hMSC-derived mitochondria as a nano-biotherapy for gastrointestinal wound healing using a rat model of post-operative fistula. Structurally intact mitochondria were isolated from hMSCs and either applied to human colonic epithelial cells (HCEC-1CT) in vitro or transplanted locally into fistula-bearing rats. Mitochondrial treatment led to a dose-dependent increase in cellular metabolic activity, intracellular ATP levels, and mitochondrial uptake by recipient cells. In vivo, mitochondrial transplantation significantly accelerated fistula closure and tissue regeneration compared to controls. These findings underscore the translational promise of mitochondria-based, cell-free therapies and lay the groundwork for future regenerative strategies targeting gastrointestinal wound repair.