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

J Yao, PJ Guihard, X Wu, AM Blazquez-Medela… - Journal of Cell …, 2017 - rupress.org
J Yao, PJ Guihard, X Wu, AM Blazquez-Medela, MJ Spencer, M Jumabay, P Tontonoz
Journal of Cell Biology, 2017rupress.org
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 …
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.
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