Stem cell- and extracellular vesicle-based therapies for perianal fistulizing Crohn's disease: An updated review.

Perianal fistulizing Crohn's disease (PFCD) is a complication of CD that significantly impacts patients' quality of life, particularly their social and sexual well-being. Despite advances in therapy, its treatment remains a major challenge in the field of inflammatory bowel disease. The pathogenesis of PFCD involves increased production of inflammatory cytokines by infiltrating macrophages and lymphocytes, stimulation of the epithelial-to-mesenchymal transition, activation of myofibroblasts, and elevated levels of matrix metalloproteinases. Mesenchymal stem cells (MSCs) are multipotent stromal cells with self-renewal and differentiation capabilities. Evidence from animal models and clinical trials indicates that MSC injection into PFCD lesions suppresses the infiltration of inflammatory cells and cytokines, resulting in complete fistula healing. More recently, MSC-derived extracellular vesicles (EVs) have shown promising results in promoting fistula healing, particularly in cases of refractory or relapsing fistulas. Notably, the activation of macroautophagy (hereafter referred to as autophagy) in MSCs has been shown to accelerate the healing process. This narrative review discusses the mechanisms underlying PFCD pathogenesis, the therapeutic roles of MSCs and their EVs, and the potential role of autophagy upregulation in enhancing MSC function and EV production.