The emerging role of intestinal stem cells in ulcerative colitis

Abstract

Ulcerative colitis (UC) is a chronic idiopathic inflammatory disease affecting the colon and rectum. Characterized by recurrent attacks, UC is often resistant to traditional anti-inflammatory therapies, imposing significant physiological, psychological, and economic burdens on patients. In light of these challenges, innovative targeted therapies have become a new expectation for patients with UC. A crucial pathological feature of UC is the impairment of the intestinal mucosal barrier, which underlies aberrant immune responses and inflammation. Intestinal stem cells (ISCs), which differentiate into intestinal epithelial cells, play a central role in maintaining this barrier. Growing studies have proved that regulating the regeneration and differentiation of ISC is a promising approach to treating UC. Despite this progress, there is a dearth of comprehensive articles describing the role of ISCs in UC. This review focuses on the importance of ISCs in maintaining the intestinal mucosal barrier in UC and discusses the latest findings on ISC functions, markers, and their regulatory mechanisms. Key pathways involved in ISC regulation, including the Wnt, Notch, Hedgehog (HH), Hippo/Yap, and autophagy pathways, are explored in detail. Additionally, this review examines recent advances in ISC-targeted therapies for UC, such as natural or synthetic compounds, microbial preparations, traditional Chinese medicine (TCM) extracts and compounds, and transplantation therapy. This review aims to offer novel therapeutic insights and strategies for patients who have long struggled with UC.

Keywords: immune response; inflammation; intestinal mucosal barrier; intestinal stem cells (ISCs); ulcerative colitis (UC).

FIGURE 1

Diagram of the healthy intestinal barrier and its impairment during ulcerative colitis (UC) (By Figdraw). (1) Healthy bowel: The mucin layer protects the epithelial surface, helping to regulate the intestinal microbial environment and preventing harmful bacteria from directly contacting the epithelial layer. Tight junctions with defensive properties maintain the intact structure of the epithelial layer. The intestinal stem cells (ISCs) renew effectively within the epithelium. And there is no immune cell aggregation in the healthy lamina propria. (2) UC: The beneficial substances in the mucin layer are reduced, along with the imbalance of intestinal flora caused by the disruption of intestinal homeostasis. Destructive flora increases and further damages the epithelial layer through direct contact with it. In the epithelial layer, the regeneration of ISCs and the tight junctions are disintegrated. The inflamed lamina propria showed a large number of immune cells.

FIGURE 2

The fate of intestinal stem cells (ISCs) in homeostasis (By Figdraw). (A) In a homeostatic environment, the progeny of ISCs continuously migrate from the base of the crypt to the intestinal lumen, proliferate and differentiate into various types of cells, while stemness gradually decreases. The normal regeneration of ISCs ensures a constant replenishment of mature intestinal epithelial cells with extremely short lifespans. (B) LGR5-positive ISCs (LGR5⁺ ISC) and quiescent ISC have some mutual conversion modes. In a homeostatic environment, ISC divide asymmetrically, producing both primary stem cell and committed progenitor cell. The latter one then differentiated upward by stages of the transient amplifying intermediates into other terminally differentiated cells with specific functions and structures, including absorptive enterocytes, deep crypt-secreting cells, tuft cells, goblet cells, and enteroendocrine cells.

FIGURE 3

Hypothetical comprehensive regulatory mechanisms of intestinal stem cells (ISCs) in ulcerative colitis (UC) (By Figdraw). (1) The classical Wnt pathway is a trimer composed of Wnt proteins, frizzled receptors, and low density lipoprotein receptor (LRP) that recruits Disheveled (DVL) to the plasma membrane and degrades the β-catenin protein-related complex; subsequently, the accumulated β-catenin protein in the cytoplasm is transferred to the nucleus; finally, the active complex formed by β-catenin protein with T cell factor (TCF)/LEF protein initiates transcription of target genes. The Wnt/Ca²⁺ pathway is activated by DVL recruitment after binding of Wnt to Frz; this is followed by activation of PLC, which promotes the production of calcium ions; subsequently, calcium ions dephosphorylate CaN to act on NFAT in the nucleus, thereby initiating transcription of target genes. Complex interactions exist between Shh protein and Wnt signaling, as well as Notch signaling, which require further investigation. (2) In the Notch pathway, the cross-linking of Notch ligand and Notch receptor initiates the cleavage of Notch receptor and produces the cleavage product, the NICD; After NICD is transferred to the nucleus, it forms a binary complex with RBP-JK to initiate transcription of target genes; with MAML binding to this binary complex, expression of specific genes such as Hes is activated. (3) SAV1 binds to the kinase MST1/2 in the Hippo pathway to enhance kinase activity, and this complex subsequently phosphorylates the complex product of LATS1/2 with MOB1, up to which point YAP/TAZ is inactivated upon phosphorylation; phosphorylation of YAP inhibits Wnt signaling to hinder stem cell regeneration; this will lead to ISC differentiation into goblet cells rather than proliferation. When the upstream signal was blocked, the inactivated YAP/TAZ transferred to the nucleus and acted on transcription factors such as TEAD and TEF to initiate transcription of target genes. (4) Autophagy of ISCs affects the repair of damaged intestinal epithelium. Frz, frizzled; LEF, lymphoid enhancer factor; PLC, Phospholipase C; CaN, calcineurin; NFAT, nuclear factor of activated T-cells; NICD, Notch intracellular domain; RBP-JK, recombination signal binding protein-Jk; MAML, mastermind-like; SAV1, salvador homolog 1; MOB1, MOB kinase activator 1A; TEAD, transcriptional enhancer associated domain; TEF, transcriptional enhancer factor.