Roles of intestinal stem cells in inflammatory bowel disease pathogenesis

Abstract

Inflammatory bowel disease (IBD), consisting primarily of ulcerative colitis and Crohn's disease, is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. The pathogenesis of IBD has been thoroughly studied throughout the past few decades, such as defective gut epithelial barrier, immune responses, genetic predisposition, infections, and dysbiosis. Recent studies have revealed the unexpected importance of intestinal stem cells (ISCs) in the pathophysiology of IBD. The rapid recovery and continuous self-renewal of intestinal epithelial cells depend on ISCs within the crypts. Proliferation and differentiation of ISCs is an important cytological basis for repairing damaged intestinal mucosa. Unfortunately, as a new therapeutic goal in IBD, mucosal healing is difficult to achieve with current treatments. Stem cell therapy is an emerging treatment for IBD that allows mucosal healing by rebuilding the mucosal barrier. In this review, we present the current research progress on the role of ISCs in IBD and discuss stem cell-based therapies that have been specifically designed for its treatment.

Keywords: Clinical application; Inflammatory bowel disease; Intestinal stem cells; Pathogenesis; Therapy potential.

Figure 1

Intestinal stem cell niche and cell types in crypt-villus structures. A: The intestinal crypt-villus axis and neighboring niche cells; B: Fibroblast growth factor binding protein 1 positive intestinal stem cells regenerate all lineages and leucine-rich repeat-containing G protein-coupled receptor 5 positive cells. Fibroblast growth factor binding protein 1 secreted by upper crypt intestinal stem cells is essential for intestinal epithelial regeneration. Images created with BioRender.com (Supplementary material). ISCs: Intestinal stem cells; Fgfbp1: Fibroblast growth factor binding protein 1; Lgr5: Leucine-rich repeat-containing G protein-coupled receptor 5; CBC: Crypt based columnar cell.

Figure 2

Key signaling pathways orchestrate stem cell fate regulation. At the crypt base, mesenchymal cells and Paneth cells secrete Wnt ligands and R-spondins to sustain the stemness and proliferation of intestinal stem cells (ISCs). Mesenchymal cells also produce bone morphogenetic protein inhibitors, promoting the self-renewal of ISCs. Epidermal growth factor, derived from Paneth cells, promotes ISC proliferation, survival, and long-term organoid growth. In addition to Wnt and epidermal growth factor, Paneth cells provide critical Notch signals to ISCs, with Notch signaling orchestrating the balance between absorptive and secretory lineage commitment. Images created with BioRender.com (Supplementary material). BMP: Bone morphogenetic protein; EGF: Epidermal growth factor; RSPOs: R-spondins.

Figure 3

Endoscopic intestinal stem cell transplantation: Therapeutic potential in inflammatory bowel disease. Images created with BioRender.com (Supplementary material). IBD: Inflammatory bowel disease.