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Interconversion between intestinal stem cell populations in distinct niches.

ABSTRACT: Intestinal epithelial stem cell identity and location have been the subject of substantial research. Cells in the +4 niche are slow-cycling and label-retaining, whereas a different stem cell niche located at the crypt base is occupied by crypt base columnar (CBC) cells. CBCs are distinct from +4 cells, and the relationship between them is unknown, though both give rise to all intestinal epithelial lineages. We demonstrate that Hopx, an atypical homeobox protein, is a specific marker of +4 cells. Hopx-expressing cells give rise to CBCs and all mature intestinal epithelial lineages. Conversely, CBCs can give rise to +4 Hopx-positive cells. These findings demonstrate a bidirectional lineage relationship between active and quiescent stem cells in their niches.

SUBMITTER: Takeda N

PROVIDER: S-EPMC3705713 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Interconversion between intestinal stem cell populations in distinct niches.

Takeda Norifumi N Jain Rajan R LeBoeuf Matthew R MR Wang Qiaohong Q Lu Min Min MM Epstein Jonathan A JA

Science (New York, N.Y.) 20111110 6061

Intestinal epithelial stem cell identity and location have been the subject of substantial research. Cells in the +4 niche are slow-cycling and label-retaining, whereas a different stem cell niche located at the crypt base is occupied by crypt base columnar (CBC) cells. CBCs are distinct from +4 cells, and the relationship between them is unknown, though both give rise to all intestinal epithelial lineages. We demonstrate that Hopx, an atypical homeobox protein, is a specific marker of +4 cells. ...[more]

PMID: 22075725

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Project description:Stomach and intestinal epithelial cells are maintained by the activity of stem cells located in the isthmus and crypt, respectively1,2. Recent studies have demonstrated a surprisingly conserved role for Wnt signaling in stomach and intestinal development and stem cells3,4. Although accumulating evidence suggests that intestinal stromal cells secrete Wnt ligands to promote stem cell renewal5-10, the source of stomach Wnt ligands is still unclear. Moreover, how these gastrointestinal stem cell niche signals are produced is currently unknown. By performing single cell analysis of gastrointestinal stromal cells, we identified cell populations with transcriptome signatures that are conserved between the stomach and intestine. In close proximity to gastrointestinal epithelial cells, these cells highly expressed pericyte markers and Wnt ligands. They also were enriched for Hh signaling, which plays a key role in gut development11,12. A recent study has shown that intestinal pericryptal cells co-express Hh target and Wnt ligand genes8. To define their relationship, we analyzed mice with Hh gain of function in the pericyte-like stromal cells conserved between the stomach and intestine, and found increased levels of Wnt ligands, supporting Hh regulation of stromal Wnt ligand expression. Moreover, utilizing Sufu and Spop double knockout mice, which stabilized GLI2, a key Hh mediator in the gut, we were able to map GLI2 binding sites genome-wide and analyze super enhancers. This work demonstrates GLI2 activation of stromal Wnt ligands through enhancers that are conserved between the stomach and intestine. To determine the significance of Wnt secreting gastrointestinal stromal cells, we genetically inhibited Wnt secretion from the perictye-like or broad stromal cells, demonstrating their roles in gastrointestinal regeneration and development, respectively. Our work not only identifies the conserved gastrointestinal stromal niche cell populations but also reveals their underlying signaling and epigenetic mechanisms.

Dataset Information

Interconversion between intestinal stem cell populations in distinct niches.

Publications

Interconversion between intestinal stem cell populations in distinct niches.

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