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

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

Author information

1
Texas Heart Institute, Cardiomyocyte Renewal Lab, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
2
Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
3
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Shanghai Children's Medical Center, Shanghai 200127, China.
4
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
5
Texas Heart Institute, Cardiomyocyte Renewal Lab, Houston, TX 77030, USA.
6
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA.
7
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA; Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada.
8
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA.
9
Texas Heart Institute, Cardiomyocyte Renewal Lab, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA; Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jfmartin@bcm.edu.

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

PMID:
29689192
PMCID:
PMC5947860
DOI:
10.1016/j.devcel.2018.03.019
[Indexed for MEDLINE]
Free PMC Article

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