Journal Article

Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis

Logan, Catriona Y., Kapalczynska, Marta, Wiedenmann, Bertram, Berger, Hilmar, Amieva, Manuel R., Mollenkopf, Hans-Joachim, Sigal, Michael, Nusse, Roeland, Meyer, Thomas F.

2017

Overview

Myofibroblast-derived R-spondin 3 orchestrates regeneration of antral stomach epithelium via Wnt signalling in Axin2 + stem cells. Sustaining stomach tissue Regeneration of the stomach epithelium is thought to be driven by long-lived stem cells residing in a niche that is yet to be defined and which can be activated in response to gastric pathogens, such as Helicobacter pylori , through an unknown mechanism. Thomas Meyer and colleagues now show that Wnt target gene expression is constrained to a restricted region of the stomach encompassing Lgr5 + stem cells. The myofibroblasts adjacent to this region provide R-spondin 3 to the stem cell compartment. R-spondin 3 is able to convert Lgr5 − cells to Lgr5 + cells. The authors also find that Helicobacter pylori infection stimulates the expression of R-spondin 3 in myofibroblasts. This control of epithelial stem cell dynamics by stromal niche cells illustrates the sophisticated mechanism behind epithelial regeneration. The constant regeneration of stomach epithelium is driven by long-lived stem cells 1 , 2 , 3 , but the mechanism that regulates their turnover is not well understood. We have recently found that the gastric pathogen Helicobacter pylori can activate gastric stem cells and increase epithelial turnover 4 , while Wnt signalling is known to be important for stem cell identity and epithelial regeneration in several tissues 5 . Here we find that antral Wnt signalling, marked by the classic Wnt target gene Axin2 , is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5 + cells, as well as adjacent, highly proliferative Lgr5 − cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5 + population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin 3 produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2 + /Lgr5 − but not Lgr5 + cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2 + cell pool to cause hyperproliferation and gland hyperplasia. The ability of stromal niche cells to control and adapt epithelial stem cell dynamics constitutes a sophisticated mechanism that orchestrates epithelial regeneration and maintenance of tissue integrity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 631/532/2118 / 64/110 / 692/699/1503 / Animals / Axin Protein - metabolism / Cell Proliferation / Epithelial Cells - cytology / Epithelium / Gastric glands / Glands / Helicobacter Infections - metabolism / Helicobacter Infections - microbiology / Helicobacter Infections - pathology / Helicobacter pylori / Helicobacter pylori - pathogenicity / Homeostasis / Humanities and Social Sciences / Hyperplasia / letter / Male / Mice / Mice, Inbred C57BL / multidisciplinary / Myofibroblasts - cytology / Myofibroblasts - metabolism / Physiological aspects / Physiological research / Pyloric Antrum - metabolism / Receptors, G-Protein-Coupled - metabolism / Regeneration / Science / Signaling / Smooth muscle / Stem Cell Niche / Stem cells / Stem Cells - cytology / Stem Cells - metabolism / Stomach / Stomach - cytology / Stroma / Stromal Cells - cytology / Stromal Cells - metabolism / Studies / Thrombospondins - metabolism / Wnt protein / Wnt Signaling Pathway