Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals

Abstract

The discovery of Lgr5+ intestinal stem cells (ISCs) triggered a breakthrough in the field of ISC research. Lgr5+ ISCs maintain the homeostasis of the intestinal epithelium in the steady state, while these cells are susceptible to epithelial damage induced by chemicals, pathogens, or irradiation. During the regeneration process of the intestinal epithelium, more quiescent +4 stem cells and short-lived transit-amplifying (TA) progenitor cells residing above Lgr5+ ISCs undergo dedifferentiation and act as stem-like cells. In addition, several recent reports have shown that a subset of terminally differentiated cells, including Paneth cells, tuft cells, or enteroendocrine cells, may also have some degree of plasticity in specific situations. The function of ISCs is maintained by the neighboring stem cell niches, which strictly regulate the key signal pathways in ISCs. In addition, various inflammatory cytokines play critical roles in intestinal regeneration and stem cell functions following epithelial injury. Here, we summarize the current understanding of ISCs and their niches, review recent findings regarding cellular plasticity and its regulatory mechanism, and discuss how inflammatory cytokines contribute to epithelial regeneration.

Keywords: Notch; Wnt; cytokines; dedifferentiation; intestinal stem cells (ISCs).

Figure 1

Intestinal stem cells and their niches. Lgr5+ crypt base columnar (CBC) cells reside at the crypt base and continuously supply their daughter cells from crypt to villi. Paneth cells, interspersed between Lgr5+ CBC cells, can act as a stem cell niche to maintain the stem cell functions of CBC cells. There is another stem cell pool, the +4 cells, which contain quiescent +4 stem cells, Paneth cell precursors, and label-retaining cells. Transit-amplifying (TA) cells include more differentiated and actively proliferating but relatively short-lived cell populations, including both secretory and absorptive progenitors, which can give rise to stem-like cells following stem cell damage. Secretory progenitors are differentiated into Paneth cells, goblet cells, tuft cells, and enteroendocrine cells, while absorptive progenitors enterocytes. The stromal cells surrounding the crypt region contribute to the stem cell niche and are classified into several subsets, such as fibroblasts, myofibroblasts, telocytes, and trophocytes, all of which express and secrete stem cell niche factors. Representative markers of each cell are shown in red.

Figure 2

Stem cell niches and regulatory signals. Stem cell niches consist of epithelial cells, stromal cells, immune cells, bacteria, the nervous system, and other signals. Paneth cells, interspersed between Lgr5+ CBC cells, secrete EGF, TGFα, DLL4, and WNT3 and maintain stem cell functions. When Paneth cells are ablated, tuft and enteroendocrine cells act as a complementary source of Notch signaling. Fibroblasts maintain stem cell functions by producing WNT, R-spondin, gremlin, and PGE2. Foxl1+Pdgfra^High telocytes provide Wnt, R-spondin, and BMP, while CD81+Pdgfra^Low trophocytes at the crypt bottom secrete BMP antagonists and gremlin 1 to strengthen WNT signaling. WNT and BMP antagonists are also secreted from smooth muscles. The cytokines secreted from immune cells, including Wnt-producing macrophages, Jagged-producing dendritic cells, IL13-producing ILC2s, and IL22-producing ILC3s, have an important role in stem cell regulation and epithelial regeneration. Enteric bacteria either directly or indirectly regulate stem cell functions via production of MDP, which supports ISC survival and activation of the tuft cell–ILC2 immune circuit through their metabolites. Tuft cells are involved in the activation of ILC2s via production of IL-25 and leukotrienes. Enteric nerves and tuft cells support ISC functions via production of acetylcholine, and various neuron-derived products can stimulate ILC2s, which support ISC function. Major signals provided from stem cell niches are shown in blue.