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.