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

Figure 1 Mechanisms of perianal fistulizing Crohn’s disease and therapeutic roles of mesenchymal stem cells[2]. Enhanced production of inflammatory cytokines by infiltrating macrophages and other inflammatory cells stimulates the epithelial-to-mesenchymal transition, resulting in activation of myofibroblasts and elevation of matrix metalloproteinases, leading to fistula formation. Injection of mesenchymal stem cells into the fistula results in suppression of the inflammatory cells and cytokines and complete resolution of perianal fistulizing Crohn’s disease. MSCs: Mesenchymal stem cells; TNF: Tumor necrosis factor; IL: Interleukin; TGF: Transforming growth factor; MMP: Matrix metalloproteinase; Th: T helper cells; TFF: Trefoil factor family; DC: Dendritic cell; NK: Natural killer; CD4: Cluster of differentiation 4; Treg: Regulatory T cell; IDO: Indolamine 2,3-dioxygenase; PDL-1: Programmed death ligand 1; PGE2: Prostaglandin E2; NO: Nitrogen oxide; GAL: Gallic acid; HO-1: Heme oxygenase-1; HLA: Human leukocyte antigen. Citation: Bhatnagar P, Elhariri S, Burud IAS, Eid N. Perianal fistulizing Crohn’s disease: Mechanisms and treatment options focusing on cellular therapy. World J Gastroenterol 2025; 31: 100221. Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc.

Figure 2 Upregulation of degradative and secretory autophagy in mesenchymal stem cells promotes their survival and enhances both the quality and quantity of their extracellular vesicles, including exosomes. Light chain 3 (LC3)-dependent extracellular vesicle (EV) loading and secretion, LC3-dependent EV loading and secretion, lysosome, autophagosome. mTOR: Mammalian target of rapamycin; AMPK: Adenosine 5’-monophosphate-activated protein kinase; MSCs: Mesenchymal stem cells; EV: Extracellular vesicle; LDELS: Light chain 3-dependent extracellular vesicle loading and secretion; PFCD: Perianal fistulizing Crohn’s disease.