BMP gradient along the intestinal villus axis controls zonated enterocyte and goblet cell states
Beumer, Joep; Puschhof, Jens; Yengej, Fjodor Yousef; Zhao, Lianzheng; Martinez-Silgado, Adriana; Blotenburg, Marloes; Begthel, Harry; Boot, Charelle; van Oudenaarden, Alexander; Chen, Ye Guang; Clevers, Hans
(2022) Cell Reports, volume 38, issue 9
(Article)
Abstract
Intestinal epithelial cells derive from stem cells at the crypt base and travel along the crypt-villus axis to die at the villus tip. The two dominant villus epithelial cell types, absorptive enterocytes and mucous-secreting goblet cells, are mature when they exit crypts. Murine enterocytes switch functional cell states during migration
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along the villus. Here, we ask whether this zonation is driven by the bone morphogenetic protein (BMP) gradient, which increases toward the villus. Using human intestinal organoids, we show that BMP signaling controls the expression of zonated genes in enterocytes. We find that goblet cells display similar zonation involving antimicrobial genes. Using an inducible Bmpr1a knockout mouse model, we confirm that BMP controls these zonated genes in vivo. Our findings imply that local manipulation of BMP signal strength may be used to reset the enterocyte “rheostat” of carbohydrate versus lipid uptake and to control the antimicrobial response through goblet cells.
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Keywords: BMP signaling, CRISPR-Cas9, enterocytes, intestinal differentiation, organoids, single-cell RNA sequencing, Animals, Bone Morphogenetic Proteins/metabolism, Intestinal Mucosa/metabolism, Intestine, Small/metabolism, Cell Differentiation, Mice, Goblet Cells, Enterocytes/metabolism, General Biochemistry,Genetics and Molecular Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: We acknowledge financial support from the ERC Advanced Grant GutHormones ( 101020405 ), the Netherlands Organ-on-Chip Initiative ( 024.003.001 ) from the Netherlands Organisation for Scientific Research (NWO), the NWO building blocks of life project: cell dynamics within lung and intestinal organoids ( 737.016.009 ) and the Gravitation Program “Materials Driven Regeneration,” funded by the Netherlands Organisation for Scientific Research ( 024.003.013 ), and the CRUK grant OPTIMISTICC ( C10674/A27140 ). F.Y.Y. acknowledges the support of the partners of “ Regenerative Medicine Crossing Borders ” (RegMed XB), Powered by Health∼Holland, Top Sector Life Sciences & Health . F.Y.Y. is grateful for the support of Maarten B. Rookmaaker and Marianne C. Verhaar from the Department of Nephrology and Hypertension, University Medical Center, Utrecht . Funding Information: We acknowledge financial support from the ERC Advanced Grant GutHormones (101020405), the Netherlands Organ-on-Chip Initiative (024.003.001) from the Netherlands Organisation for Scientific Research (NWO), the NWO building blocks of life project: cell dynamics within lung and intestinal organoids (737.016.009) and the Gravitation Program ?Materials Driven Regeneration,? funded by the Netherlands Organisation for Scientific Research (024.003.013), and the CRUK grant OPTIMISTICC (C10674/A27140). F.Y.Y. acknowledges the support of the partners of ?Regenerative Medicine Crossing Borders? (RegMed XB), Powered by Health?Holland, Top Sector Life Sciences & Health. F.Y.Y. is grateful for the support of Maarten B. Rookmaaker and Marianne C. Verhaar from the Department of Nephrology and Hypertension, University Medical Center, Utrecht. J.B. J.P. F.Y.Y. and H.C. conceptualized the project, designed the experiments, performed analyses, interpreted the results, and wrote the manuscript. C.B. and H.B. assisted in data acquisition. C.B. M.B. and A.v.O. performed analyses on in situ and single-cell RNA-seq data. A.M.-S. assisted in cell culture experiments and was supervised by J.B. J.P. and H.C. L.Z. and Y.-G.C. performed the mouse experiments. H.C. is inventor on several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/. J.B. and H.C. are inventors on a patent related to this work (improved differentiation method, publication number 20210047618). Publisher Copyright: © 2022 The Author(s) Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
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