Please use this identifier to cite or link to this item: https://doi.org/10.1073/pnas.1713510115
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dc.titlePDGFR alpha(+) pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo
dc.contributor.authorGreicius, Gediminas
dc.contributor.authorKabiri, Zahra
dc.contributor.authorSigmundsson, Kristmundur
dc.contributor.authorLiang, Chao
dc.contributor.authorBunte, Ralph
dc.contributor.authorSingh, Manvendra K
dc.contributor.authorVirshup, David M
dc.date.accessioned2021-09-27T08:17:47Z
dc.date.available2021-09-27T08:17:47Z
dc.date.issued2018-04-03
dc.identifier.citationGreicius, Gediminas, Kabiri, Zahra, Sigmundsson, Kristmundur, Liang, Chao, Bunte, Ralph, Singh, Manvendra K, Virshup, David M (2018-04-03). PDGFR alpha(+) pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115 (14) : E3173-E3181. ScholarBank@NUS Repository. https://doi.org/10.1073/pnas.1713510115
dc.identifier.issn00278424
dc.identifier.issn10916490
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/201149
dc.description.abstractWnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5-expressing intestinal stem cells. However, in vivo, Paneth cell and indeed all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem-cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis. RSPO3 is highly expressed in pericryptal myofibroblasts in the lamina propria and is several orders of magnitude more potent than RSPO1 in stimulating both Wnt/β-catenin signaling and organoid growth. Stromal Rspo3 ablation ex vivo resulted in markedly decreased organoid growth that was rescued by exogenous RSPO3 protein. Pdgf receptor alpha (PdgfRα) is known to be expressed in pericryptal myofibroblasts. We therefore evaluated if PdgfRα identified the key stromal niche cells. In vivo, Porcn excision in PdgfRα+ cells blocked intestinal crypt formation, demonstrating that Wnt production in the stroma is both necessary and sufficient to support the intestinal stem-cell niche. Mice with Rspo3 excision in the PdgfRα+ cells had decreased intestinal crypt Wnt/β-catenin signaling and Paneth cell differentiation and were hypersensitive when stressed with dextran sodium sulfate. The data support a model of the intestinal stem-cell niche regulated by both Wnts and RSPO3 supplied predominantly by stromal pericryptal myofibroblasts marked by PdgfRα.
dc.language.isoen
dc.publisherNATL ACAD SCIENCES
dc.sourceElements
dc.subjectScience & Technology
dc.subjectMultidisciplinary Sciences
dc.subjectScience & Technology - Other Topics
dc.subjectWnt signaling
dc.subjectstroma
dc.subjectmyofibroblasts
dc.subjectintestine
dc.subjectR-spondins
dc.subjectR-SPONDIN
dc.subjectPANETH CELLS
dc.subjectSELF-RENEWAL
dc.subjectPDGFR-ALPHA
dc.subjectCOLON
dc.subjectMOUSE
dc.subjectDIFFERENTIATION
dc.subjectCANCER
dc.subjectNICHE
dc.subjectMICE
dc.typeArticle
dc.date.updated2021-09-22T02:24:38Z
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1073/pnas.1713510115
dc.description.sourcetitlePROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
dc.description.volume115
dc.description.issue14
dc.description.pageE3173-E3181
dc.published.statePublished
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