The Role of Secretome from Mesenchymal Stromal Cells in Promoting Nerve Regeneration After Neurotmesis

IntroductionNeurotmesis, the most severe form of peripheral nerve injury, remains a significant clinical challenge due to limited intrinsic regenerative capacity and suboptimal outcomes of current therapies. Mesenchymal stromal cells (MSCs) secretome has emerged as a promising cell-free alternative, providing neurotrophic and immunomodulatory factors to support nerve repair while avoiding the limitations of cell transplantation. This study aimed to evaluate the regenerative efficacy of primed adipose-derived MSC secretome in a rat model of sciatic nerve neurotmesis. Materials and MethodsHuman and rat adipose-derived MSCs were cultured and primed under hypoxic and inflammatory conditions. Secretomes were characterized by nanoparticle tracking analysis, proteomics, and total protein quantification. Neurotmesis was induced in Wistar rats, followed by repair with biomaterial alone or combined with human or rat secretome. Functional recovery was assessed by neurophysiological measurements (CMAP, NAP) at 6 months. Molecular and protein analyses included qPCR for myelination genes and ELISA for NGF. Morphological regeneration was evaluated by histology, immunofluorescence, and transmission electron microscopy (TEM). ResultsSecretome priming enhanced the secretion of neurotrophic factors (GDNF, VEGFA, FGF2) and immunomodulatory proteins (IL6, CCL2), as confirmed by transcriptomic and proteomic analyses. In vivo, secretome-treated groups showed significantly improved neurophysiological recovery, with restoration of CMAP/NAP amplitudes and increased NGF levels. qPCR revealed upregulation of myelination-associated genes (MPZ, Krox-20, c-Jun) in treated nerves. Histological and TEM analyses demonstrated robust axonal regeneration, thicker myelin sheaths, and the presence of Remak bundles. ConclusionsPrimed MSC secretome markedly enhances structural and functional recovery after sciatic nerve neurotmesis, supporting its potential as a safe, effective, and scalable cell-free therapy for peripheral nerve repair. These findings provide a strong rationale for further translational studies and clinical development.