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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone Morphogenetic Protein Receptors / genetics
  • Bone Morphogenetic Protein Receptors / metabolism*
  • Cell Proliferation
  • Female
  • Gene Expression Regulation*
  • Homeostasis
  • Humans
  • Intestinal Mucosa / cytology*
  • Intestinal Mucosa / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Regeneration / physiology*
  • Stem Cells / cytology*
  • Stem Cells / physiology
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway

Substances

  • Wnt Proteins
  • Bone Morphogenetic Protein Receptors