Intestinal Stem Cells and Immune Cell Relationships: Potential Therapeutic Targets for Inflammatory Bowel Diseases

Abstract

The mammalian intestine is the largest immune organ that contains the intestinal stem cells (ISC), differentiated epithelial cells (enterocytes, Paneth cells, goblet cells, tuft cells, etc.), and gut resident-immune cells (T cells, B cells, dendritic cells, innate lymphoid cell, etc.). Inflammatory bowel disease (IBD), a chronic inflammatory disease characterized by mucosa damage and inflammation, threatens the integrity of the intestine. The continuous renewal and repair of intestinal mucosal epithelium after injury depend on ISCs. Inflamed mucosa healing could be a new target for the improvement of clinical symptoms, disease recurrence, and resection-free survival in IBD treated patients. The knowledge about the connections between ISC and immune cells is expanding with the development of in vitro intestinal organoid culture and single-cell RNA sequencing technology. Recent findings implicate that immune cells such as T cells, ILCs, dendritic cells, and macrophages and cytokines secreted by these cells are critical in the regeneration of ISCs and intestinal epithelium. Transplantation of ISC to the inflamed mucosa may be a new therapeutic approach to reconstruct the epithelial barrier in IBD. Considering the links between ISC and immune cells, we predict that the integration of biological agents and ISC transplantation will revolutionize the future therapy of IBD patients.

Keywords: cytokine; immune cell; inflammatory bowel disease; intestinal stem cell; organoids.

Figure 1

Intestinal stem cells and differentiated progeny. (A) The intestinal epithelium is covered with a monolayer of epithelial cells. ISC generate TA cells in the crypts. TA cells migrate upward along the villi-crypt axis and differentiate into various epithelial cells. ISC are located at the bottom of the intestinal crypts. (B) Lgr5⁺ ISC generate TA cells, which can produce two mature epithelial cell lineages: absorptive type (enterocytes) and secretory type (goblet cells, Paneth cells, tuft cells, and enteroendocrines). +4 ISC have been proposed as a quiescent stem cell population. ISC, intestinal stem cell; TA, transit-amplifying.

Figure 2

The link between the intestinal stem cells and immune cells. The role of immune cells such as T cells and ILCs, as well as cytokines secreted by these immune cells on the regulation of ISC function. T_reg cells (IL-10) promote ISC renewal, while T_H1 (IFNγ), T_H2 (IL-4, IL-13), and T_H17 cells (IL-17A) suppress ISC renewal and promote differentiation; T_H1(IFNγ) and T_H2 (IL-4, IL-13) cells promote specific differentiation toward Paneth cells and tuft cells, respectively; donor T cells (IFNγ) act on ISC by triggering apoptosis in GVHD; MHCII is important for interactions between ISC and T cells. ILC2s (IL-4, IL-13) promote specific differentiation toward goblet cells and tuft cells; ILC3s (IL-22) promote ISC proliferation through STAT3 signals; protect ISC against genotoxic stress. IL, interleukin; IFNγ, interferon γ; ISC, intestinal stem cell; ILC, innate lymphoid cell; T_H, T helper; T_reg cells, regulatory T cells; GVHD, graft versus host disease, MHCII, major histocompatibility complex II; STAT3, signal transducer, and activator of transcription 3.

Figure 3

Intestinal organoid–immune cell co-culture models. (A) Crypts are isolated from the intestinal tissue and then embedded into Matrigel with culture medium. Intestinal organoids are formed by crypts. (B) Several intestinal organoids and immune cells and/or cytokines co-culture systems have been established. Treatment of organoids with cytokines is used to estimate the effect of immune cell-derived cytokines on intestinal epithelial cells (especially ISC). Organoids are digested to single cells and then co-cultured with immune cells, which is used to assess the interaction of immune cells and epithelial cells. The addition of (activated) immune cells, such as innate lymphoid cells or T cells, to complete organoids is used to estimate the interactions between epithelial cells and immune cells.

Figure 4

Intestinal stem cell therapy strategy in IBD. Intestinal crypts and ISCs can be harvested endoscopically from healthy intestinal mucosa in IBD patients, and then expanded in vitro by the established organoid culture method. After growing them to a desired number of cells, they can be transplanted onto the target site through an endoscopic delivery method. ISC, intestinal stem cell; IBD, inflammatory bowel disease.