Perianal fistulizing Crohn's disease: Mechanisms and treatment options focusing on cellular therapy

Abstract

Perianal fistulizing Crohn's disease (PFCD) is a common presentation of CD, which affects the patients' quality of life, including social and sexual function. The management of PFCD remains a critical challenge in inflammatory bowel disease, primarily due to limited understanding of the mechanisms involved in its pathogenesis, complicating medical treatment. Increased production of inflammatory cytokines such as tumor necrosis factor and interleukin-13 by infiltrating macrophages and other inflammatory cells stimulate the epithelial-to-mesenchymal transition, resulting in activation of myofibroblasts and elevation of matrix metalloproteinases, leading to fistula formation. Given the potential for malignant transformation, PFCD screening is critical. Cytokine and inflammation-targeted therapies can help control this disease, but recurrence is a common complication. Surgical interventions such as fistulotomy represent viable therapeutic options, with magnetic resonance imaging serving as an important diagnostic tool for delineating fistula tract anatomy. Animal models and clinical trials demonstrate that injection of mesenchymal stem cells (MSCs) into the fistula results in suppression of the inflammatory cells and cytokines and complete resolution of PFCD. Recently, MSC-derived extracellular vesicles were found to stimulate fistula healing, with encouraging results. In this article, we comment on the review article by Pacheco et al, summarizing the various lines of PFCD treatment and highlighting the role of screening for this disease. Importantly, we focus on the various mechanisms involved in the pathogenesis of PFCD, the therapeutic roles of MSCs and related extracellular vesicles, and explore the potential role of autophagy in enhancing the therapeutic efficacy of these cells, which may help in the treatment of this disease.

Keywords: Autophagy; Crohn’s disease; Extracellular vesicles; Magnetic resonance imaging; Perianal fistulas; Regenerative medicine; Stem cell therapy; Treatment outcomes.

Figure 1

Mechanisms of perianal fistulizing Crohn’s disease and therapeutic roles of mesenchymal stem cells. 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; 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.