Subepithelial telocytes are an important source of Wnts that supports intestinal crypts

Abstract

Tissues with rapid cellular turnover, such as the mammalian hematopoietic system or the intestinal epithelium, are dependent upon stem and progenitor cells, which through proliferation provide differentiated cells to maintain organismal health. Stem and progenitor cells, in turn, are thought to rely upon signals and growth factors provided by local niche cells to support their function and self-renewal. Several cell types have been proposed to provide the signals required for the proliferation and differentiation of the ISC in the crypt1–6. Here, we identify subepithelial telocytes as an important source of Wnt proteins, without which intestinal stem cells cannot proliferate and support epithelial renewal. Telocytes are large but rare mesenchymal cells that are marked by Foxl1 and PDGFRα expression and form a subepithelial plexus that extends from the stomach to the colon. While supporting the entire epithelium, Foxl1+ telocytes compartmentalize the production of Wnt ligands and inhibitors to enable localized pathway activation. Conditional gene ablation of Porcupine (Porcn), which is required for functional maturation of all Wnt proteins, in Foxl1+ telocytes causes rapid cessation of Wnt signaling to intestinal crypts, followed by loss of stem and transit amplifying cell proliferation and impaired epithelial renewal. Thus, Foxl1+ telocytes are an important source of niche signals to intestinal stem cells.

Spatial relationship between telocytes, interstitial cells of Cajal and the enteric nervous system in the human ileum and colon

“…The difference between the ileum and colon regarding the pattern and number of ICCs and TCs, around and within the ganglia, could possibly be explained by the difference in motility between the small and large bowel . The TCs have an important role in the organization and control of the extracellular matrix, structural support, intercellular communication and creation of the environment . Furthermore, TCs contribute to the regulation of the Wnt pathway in regeneration and through toll‐like receptors in immunoregulation .…”

“…TCs have been localized in several other organs as well . Several investigations have suggested that TCs and PDGFRα‐positive cells influence the intestinal motility, among many other functions …”

Expression of toll‐like receptors and their regulatory roles in murine cardiac telocytes

“…In greater detail, Olga simionescu and colleagues demonstrated that telocytes maintained in close contact with mast cells, macrophages and mononuclear cells by their long telopode and an apoptotic telocyte with condensed chromatin has been found in the vicinity of a dendritic cell in psoriasis . Although a few studies have reported the function of telocytes, little is known about the relationship between telocytes and other cells. We found that the level of iNOS was significantly increased after TLR2 activation (Figure C,), suggesting that activated telocytes had enhanced the ability of immunosuppression.…”

Dermal Condensate Niche Fate Specification Occurs Prior to Formation and Is Placode Progenitor Dependent

“…In many cases, signals are derived from specialized niche cells that control stem cell quiescence for long periods of time, regulate stem cell self-renewal, or guide their differentiation into one or more lineages of the respective tissue. Neighboring niche cell types and their signals have been identified in several tissues such as bone marrow (Wei and Frenette, 2018), intestine (Shoshkes-Carmel et al, 2018), brain (Falk and Götz, 2017), lung (Lee et al, 2017) and skin (Ge and Fuchs, 2018; Sennett and Rendl, 2012). But a detailed understanding of the molecular controls of niche fate specification during embryonic development remains limited.…”