The Intestinal Stem Cell Niche: A Central Role for Foxl1-Expressing Subepithelial Telocytes

Abstract

The columnar epithelium of the alimentary tract, extending from stomach to colon, is constantly renewed by proliferation of stem and progenitor cells, which give rise to the various differentiated cell types as required by the regional specification of the gut tube. Proliferation occurs in specific zones, which in the intestine form crypts that reach into the underlying stroma. Cellular replication in the crypt is supported by an intestinal stem cell niche, the identity of which has long been controversial. Multiple recent studies have identified subepithelial telocytes, marked by expression of the winged helix transcription factor Foxl1 and the hedgehog signaling mediator Gli1, as the critical source of pro-proliferative Wnt signals to the stem/progenitor cell compartment. This review attempts to summarize and integrate these findings.

Keywords: Foxl1; Stem Cell Niche; Telocyte; Winged Helix Transcription Factors.

Figure 1

Foxl1⁺telocytes establish a subepithelial plexus immediately underneath the gastrointestinal epithelium. (A) Nuclei of telocytes in the mouse jejunum are labeled by Foxl1 immunostaining (red). EpCAM (green) outlines epithelial cells, and DAPI (blue) outlines all nuclei. Reprinted with permission from Aoki et al. (B) Nuclei of telocytes in the mouse glandular stomach are labeled by Foxl1 immunostaining (red). EpCAM (green) outlines epithelial cells, and DAPI (blue) outlines all nuclei. (C) Confocal imaging of X-Clarity (Logos Biosystems, Anyang-si, Gyeonggi-do, South Korea) cleared mouse jejunum demonstrates the telocyte plexus, here visualized by platelet-derived growth factor receptor-alpha staining (green) that underlies all epithelial cells. EpCAM (red) was used to label epithelial cells. Reprinted with permission from Shoshkes-Carmel et al.

Figure 2

Foxl1⁺telocytes are closely appositioned to the intestinal epithelium and compartmentalize production of key signaling molecules along the crypt-villus axis. Foxl1/Gli1 positive telocytes are large, thin cells that form a continuous plexus underneath the gastric and intestinal epithelium. Telocytes compartmentalize production of signaling molecules such that expression of pro-proliferative factors such as R-Spondin and Wnt2b is highest in the crypt, and that of pro-differentiation factors such as BMP5 and Wnt5a is highest in the villi, thus supporting both intestinal regeneration as well as differentiation.