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Dev Cell. 2018 Mar 12;44(5):624-633.e4. doi: 10.1016/j.devcel.2018.01.024. Epub 2018 Mar 1.

Enteroid Monolayers Reveal an Autonomous WNT and BMP Circuit Controlling Intestinal Epithelial Growth and Organization.

Author information

1
Green Center for Systems Biology, Simmons Cancer Center, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
2
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Green Center for Systems Biology, Simmons Cancer Center, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: lani.wu@ucsf.edu.
5
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: steven.altschuler@ucsf.edu.

Abstract

The intestinal epithelium maintains a remarkable balance between proliferation and differentiation despite rapid cellular turnover. A central challenge is to elucidate mechanisms required for robust control of tissue renewal. Opposing WNT and BMP signaling is essential in establishing epithelial homeostasis. However, it has been difficult to disentangle contributions from multiple sources of morphogen signals in the tissue. Here, to dissect epithelial-autonomous morphogenic signaling circuits, we developed an enteroid monolayer culture system that recapitulates four key properties of the intestinal epithelium, namely the ability to maintain proliferative and differentiated zones, self-renew, polarize, and generate major intestinal cell types. We systematically perturb intrinsic and extrinsic sources of WNT and BMP signals to reveal a core morphogenic circuit that controls proliferation, tissue organization, and cell fate. Our work demonstrates the ability of intestinal epithelium, even in the absence of 3D tissue architecture, to control its own growth and organization through morphogen-mediated feedback.

KEYWORDS:

BMP; Wnt; crypt; epithelium; feedback; homeostasis; intestine; organoid; proliferation

Comment in

PMID:
29503158
PMCID:
PMC5849535
[Available on 2019-03-12]
DOI:
10.1016/j.devcel.2018.01.024
[Indexed for MEDLINE]

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