Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation

J Cell Biol. 2017 Oct 2;216(10):3369-3385. doi: 10.1083/jcb.201612122. Epub 2017 Aug 24.

Abstract

The vascular endothelium is critical for induction of appropriate lineage differentiation in organogenesis. In this study, we report that dysfunctional pulmonary endothelium, resulting from the loss of matrix Gla protein (MGP), causes ectopic hepatic differentiation in the pulmonary epithelium. We demonstrate uncontrolled induction of the hepatic growth factor (HGF) caused by dysregulated cross talk between pulmonary endothelium and epithelium in Mgp-null lungs. Elevated HGF induced hepatocyte nuclear factor 4 α (Hnf4a), which competed with NK2 homeobox 1 (Nkx2.1) for binding to forkhead box A2 (Foxa2) to drive hepatic differentiation in Mgp-null airway progenitor cells. Limiting endothelial HGF reduced Hnf4a, abolished interference of Hnf4a with Foxa2, and reduced hepatic differentiation in Mgp-null lungs. Together, our results suggest that endothelial-epithelial interactions, maintained by MGP, are essential in pulmonary cell differentiation.

Publication types

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

MeSH terms

  • Animals
  • Cell Communication*
  • Cell Differentiation*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism*
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism
  • Mice
  • Mice, Knockout
  • Proteins / genetics
  • Proteins / metabolism
  • Respiratory Mucosa / cytology
  • Respiratory Mucosa / metabolism*

Substances

  • Foxa2 protein, mouse
  • HGF protein, mouse
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Proteins
  • granuloma protein, mouse
  • Hepatocyte Nuclear Factor 3-beta
  • Hepatocyte Growth Factor