Exosomes derived from bone marrow-derived mesenchymal stem cells of exercise-trained mice improve wound healing by inhibiting macrophage M1 polarization.

Background: Engaging in appropriate exercise is advantageous for our well-being. We investigated whether exercise could affect the paracrine function of BMSCs and whether exosomes derived from treadmill exercise-trained mouse (Exo-tread) BMSCs could engender more pronounced effects on wound healing.

Methods: Firstly, the effects of treadmill exercise on mouse BMSCs biological functions, exosomes secretion quantity and identification were assessed. Furthermore, we assessed the effects of Exo-tread on M1 macrophage by qPCR and FCM in vitro. Additionally, the expressions and phosphorylation status of p65 and p38 proteins were analyzed via Western blotting. For the in vivo component, we induced wound models of mice. Subsequently, we assessed the effects of Exo-tread using various methodologies including imaging, H&E, Masson, immunohistochemical, and immunofluorescence staining. To demonstrate whether Exo-tread could act through macrophages, we further depleted mouse macrophages.

Results: Exercise accelerated the proliferation of BMSCs and the secretion of exosomes. In vitro, Exo-tread markedly decreased the expression of inflammatory factors, while concurrently suppressing M1 polarization in mouse peritoneal macrophages compared to the Exo-ctrl group. These observed effects were potentially mediated by the reduction in the M1 polarization ratio, achieved through the inhibition of p65 and p38 phosphorylation. Similarly, in vivo experiments demonstrated that Exo-tread significantly enhanced wound healing by attenuating inflammatory cytokines and M1 macrophages.

Conclusions: Exo-tread facilitates wound healing by mitigating the inflammatory response, achieved through a reduction in the M1 polarization ratio.