Personalized human umbilical cord mesenchymal stem cell-derived exosome pre-treatment based on the simulation of scar microenvironment characteristics: a promising approach for early scar treatment.

Abstract

BACKGROUND: Mesenchymal stem cells (MSCs) are essential for tissue repair and immunomodulation, primarily through their paracrine effects, which are influenced by the surrounding microenvironment. The observed heterogeneity in MSCs, arising from diverse sources and culture conditions, suggests that disease-specific microenvironments can modulate the paracrine effects of MSCs. This study proposes to simulate the scar microenvironment to pretreat MSCs, enabling them to produce anti-scar-specific exosomes, and to evaluate the effectiveness of these exosomes in reducing scars. The ultimate goal is to develop more effective strategies for scar treatment. METHODS: hUCMSCs were pretreated with inflammatory factors (IF) or scar tissue homogenate (STH), and their exosomes were isolated. This process yielded four types of exosomes: IF-Exos, STH-Exos, IF-STH-Exos and traditional exosomes (Tra-Exos). The impact of these exosomes on myofibroblasts and M1 macrophages were assessed through cell experiments. The anti-scar potential of these compounds was further evaluated in a rabbit ear scar model. RESULTS: Cellular experiments demonstrated that IF-STH-Exos not only inhibited the proliferation and migration of myofibroblasts but also promoted the polarization of macrophages from the M1 to M2 phenotype. Compared with other exosome groups, the IF-STH-Exos significantly reduced scar formation, reduced epithelial thickness, promoted collagen retraction, suppressed angiogenesis, and decreased both inflammation and the M1/M2 macrophage ratio in vivo. Additionally, IF-STH-Exos regulated the expression of genes involved in anti-fibrotic pathways while suppressing those linked to fibrosis. CONCLUSION: Exosomes pretreated under simulated scar microenvironment conditions can effectively mitigate scar formation by reducing inflammation and promoting anti-fibrotic processes. This study provides a novel approach to clinical anti-scar treatment.