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

• Published in: Nature (London) Vol. 548; no. 7668; pp. 451 - 455
• Main Authors: Sigal, Michael, Logan, Catriona Y., Kapalczynska, Marta, Mollenkopf, Hans-Joachim, Berger, Hilmar, Wiedenmann, Bertram, Nusse, Roeland, Amieva, Manuel R., Meyer, Thomas F.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-08-2017; Nature Publishing Group
• Subjects: 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
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature23642

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.