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Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E506-E513. doi: 10.1073/pnas.1620059114. Epub 2017 Jan 10.

CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury.

Author information

1
Unité Stroma, Inflammation & Tissue Repair, Institut Pasteur, 75724 Paris, France.
2
Unité Microenvironment & Immunity, Institut Pasteur, 75724 Paris, France.
3
INSERM U1224, 75724 Paris, France.
4
Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris, France.
5
INSERM U1202, 75724 Paris, France.
6
Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 75724 Paris, France; lucie.peduto@pasteur.fr philippe.sansonetti@pasteur.fr.
7
Chaire de Microbiologie et Maladies Infectieuses, Collège de France, 75231 Paris, France.
8
Unité Stroma, Inflammation & Tissue Repair, Institut Pasteur, 75724 Paris, France; lucie.peduto@pasteur.fr philippe.sansonetti@pasteur.fr.

Abstract

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+ αSMA- 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.

KEYWORDS:

CD34; inflammation; intestinal stem cells; mesenchymal niche

PMID:
28074039
PMCID:
PMC5278455
DOI:
10.1073/pnas.1620059114
[Indexed for MEDLINE]
Free PMC Article

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