Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development

Dev Cell. 2018 Apr 23;45(2):153-169.e6. doi: 10.1016/j.devcel.2018.03.019.

Abstract

During development, progenitors progress through transition states. The cardiac epicardium contains progenitors of essential non-cardiomyocytes. The Hippo pathway, a kinase cascade that inhibits the Yap transcriptional co-factor, controls organ size in developing hearts. Here, we investigated Hippo kinases Lats1 and Lats2 in epicardial diversification. Epicardial-specific deletion of Lats1/2 was embryonic lethal, and mutant embryos had defective coronary vasculature remodeling. Single-cell RNA sequencing revealed that Lats1/2 mutant cells failed to activate fibroblast differentiation but remained in an intermediate cell state with both epicardial and fibroblast characteristics. Lats1/2 mutant cells displayed an arrested developmental trajectory with persistence of epicardial markers and expanded expression of Yap targets Dhrs3, an inhibitor of retinoic acid synthesis, and Dpp4, a protease that modulates extracellular matrix (ECM) composition. Genetic and pharmacologic manipulation revealed that Yap inhibits fibroblast differentiation, prolonging a subepicardial-like cell state, and promotes expression of matricellular factors, such as Dpp4, that define ECM characteristics.

Keywords: Hippo signaling; epicardium; fibroblast differentiation; single-cell RNA sequencing.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Dipeptidyl Peptidase 4 / genetics
  • Dipeptidyl Peptidase 4 / metabolism
  • Extracellular Matrix
  • Female
  • Fibroblasts / cytology*
  • Fibroblasts / metabolism
  • Gene Expression Profiling
  • Heart / embryology*
  • Heart / physiology
  • Mice
  • Mice, Knockout
  • Organogenesis / physiology*
  • Pericardium / cytology*
  • Pericardium / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction
  • Single-Cell Analysis
  • Tumor Suppressor Proteins / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Tumor Suppressor Proteins
  • Yap protein, mouse
  • Alcohol Oxidoreductases
  • DHRS3 protein, mouse
  • Lats1 protein, mouse
  • Hippo protein, mouse
  • LATS2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Dipeptidyl Peptidase 4
  • Dpp4 protein, mouse