Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 4, Pages E506-E513Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1620059114
Keywords
intestinal stem cells; mesenchymal niche; inflammation; CD34
Categories
Funding
- Institut Pasteur, la Fondation pour la Recherche Medicale
- European Research Council (ERC) [648428-PERIF]
- Ministere de l'Enseignement Superieur et de la Recherche
- Fondation pour la Recherche Medicale en France [FDT20130928338]
- European Research Council [339579-DECRYPT]
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The intestinal epithelium is continuously renewed by intestinal epithelial stem cells (IESCs) positioned at the base of each crypt. Mesenchymal-derived factors are essential to maintain IESCs; however, the cellular composition and development of such mesenchymal niche remains unclear. Here, we identify pericryptal CD34(+) Gp38(+) alpha SMA(-) mesenchymal cells closely associated with Lgr5(+) IESCs. We demonstrate that CD34(+) Gp38(+) cells are the major intestinal producers of the niche factors Wnt2b, Gremlin1, and R-spondin1, and are sufficient to promote maintenance of Lgr5(+) IESCs in intestinal organoids, an effect mainly mediated by Gremlin1. CD34(+) Gp38(+) cells develop after birth in the intestinal submucosa and expand around the crypts during the third week of life in mice, independently of the microbiota. We further show that pericryptal CD34(+) gp38(+) cells are rapidly activated by intestinal injury, up-regulating niche factors Gremlin1 and R-spondin1 as well as chemokines, proinflammatory cytokines, and growth factors with key roles in gut immunity and tissue repair, including IL-7, Ccl2, Ptgs2, and Amphiregulin. Our results indicate that CD34(+) Gp38(+) mesenchymal cells are programmed to develop in the intestine after birth to constitute a specialized microenvironment that maintains IESCs at homeostasis and contribute to intestinal inflammation and repair after injury.
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