The extracellular matrix controls stem cell specification and crypt morphology in the developing and adult mouse gut

Ramadan, R. et al. (2022) The extracellular matrix controls stem cell specification and crypt morphology in the developing and adult mouse gut. Biology Open, 11(12), bio059544. (doi: 10.1242/bio.059544) (PMID:36350252) (PMCID:PMC9713296)

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The rapid of the epithelial gut lining is fueled by stem cells that reside at the base of intestinal crypts. The signal transduction pathways and morphogens that regulate intestinal stem cell self-renewal and differentiation have been extensively characterized. In contrast, although extracellular matrix (ECM) components form an integral part of the intesti­nal stem cell niche, their direct influence on the cellular compo­sition is less well understood. We set out to systematically compare the effect of two ECM classes, interstitial matrix and the basement membrane, on the intestinal epithelium. We found that both collagen I and laminin-containing cultures allow growth of small intestinal epithelial cells with all cell types present in both cultures, albeit at different ratios. The collagen cultures contained a subset of cells enriched in fetal-like markers. In con­trast, laminin increased Lgr5+ stem cells and Paneth cells, and induced crypt-like morphology changes. The transition from a collagen culture to a laminin culture, re­sembles the gut development in vivo. The ECM dramatic remodelling is accompa­nied by a local expression of the laminin receptor ITGA6 in the crypt-forming epithelium. Importantly, deletion of laminin in the adult mouse results in a marked reduction of adult intestinal stem cells. Overall, our data support the hy­pothesis that the formation of intestinal crypts is induced by an increased laminin concentration in the ECM.

Item Type:Articles
Additional Information:D.J.H. was funded by EMBO (ALTF 1102-2017) and by the KWF Kankerbestrijding Young Investigator grant 13544. J.L. was funded by the Medical Research Council (MR/N021800/1). L.V. is supported by The New York Stem Cell Foundation and grants from KWF (UVA2014-7245), the Maurits en Anna de Kock Stichting (2015-2), Worldwide Cancer Research (14-1164), the Maag Lever Darm Stichting (MLDS-CDG 14-03), the European Research Council (ERG-CoG, NIMICRY) and ZonMw (Vici). L.V. is a New York Stem Cell Foundation–Robertson Investigator. O.J.S. was funded by the Cancer Research UK grants A17196 and A21139. Open Access funding provided by Amsterdam University Medical Centers.
Glasgow Author(s) Enlighten ID:Leach, Dr Joshua and Sansom, Professor Owen
Authors: Ramadan, R., Wouters, V. M., van Neerven, S. M., de Groot, N. E., Martins, G. T., Muncan, V., Franklin, O. D., Battle, M., Carlson, K. S., Leach, J., Sansom, O. J., Boulard, O., Chamaillard, M., Vermeulen, L., Medema, J. P., and Huels, D. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Biology Open
Publisher:Company of Biologists
ISSN (Online):2046-6390
Published Online:23 November 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Biology Open 11(12):bio059544
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172879Examining the relationship between KRAS mutation and immunotherapy resistance in colorectal cancerOwen SansomMedical Research Council (MRC)MR/N021800/1CS - Beatson Institute for Cancer Research