Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome

Yifei Miao; Lei Tian; Marcy Martin; Sharon L Paige; Francisco X Galdos; Jibiao Li; Alyssa Klein; Hao Zhang; Ning Ma; Yuning Wei; Maria Stewart; Soah Lee; Jan-Renier Moonen; Bing Zhang; Paul Grossfeld; Seema Mital; David Chitayat; Joseph C Wu; Marlene Rabinovitch; Timothy J Nelson; Shuyi Nie; Sean M Wu; Mingxia Gu

doi:10.1016/j.stem.2020.07.015

Intrinsic Endocardial Defects Contribute to Hypoplastic Left Heart Syndrome

Cell Stem Cell. 2020 Oct 1;27(4):574-589.e8. doi: 10.1016/j.stem.2020.07.015. Epub 2020 Aug 17.

Authors

Yifei Miao¹, Lei Tian², Marcy Martin³, Sharon L Paige⁴, Francisco X Galdos⁴, Jibiao Li⁵, Alyssa Klein³, Hao Zhang², Ning Ma², Yuning Wei⁶, Maria Stewart⁷, Soah Lee⁴, Jan-Renier Moonen³, Bing Zhang⁸, Paul Grossfeld⁹, Seema Mital¹⁰, David Chitayat¹¹, Joseph C Wu², Marlene Rabinovitch³, Timothy J Nelson¹², Shuyi Nie⁵, Sean M Wu⁴, Mingxia Gu¹³

Affiliations

¹ Department of Pediatrics, Division of Pediatric Cardiology, Stanford School of Medicine, Stanford, CA 94305, USA; Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA; Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine, CuSTOM, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
² Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell and Regenerative Biology, Stanford School of Medicine, Stanford, CA 94305, USA.
³ Department of Pediatrics, Division of Pediatric Cardiology, Stanford School of Medicine, Stanford, CA 94305, USA; Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
⁴ Department of Pediatrics, Division of Pediatric Cardiology, Stanford School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell and Regenerative Biology, Stanford School of Medicine, Stanford, CA 94305, USA.
⁵ School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁶ Center for Personal Dynamic Regulomes, Stanford School of Medicine, Stanford, CA 94305, USA.
⁷ Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine, CuSTOM, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁸ Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai 200240, China.
⁹ Department of Pediatrics, UCSD School of Medicine, La Jolla, CA 92093, USA.
¹⁰ Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada.
¹¹ Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada; The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
¹² Division of General Internal Medicine, Division of Pediatric Cardiology, and Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
¹³ Department of Pediatrics, Division of Pediatric Cardiology, Stanford School of Medicine, Stanford, CA 94305, USA; Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA; Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Stem Cell and Organoid Medicine, CuSTOM, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. Electronic address: [email protected].

Abstract

Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease characterized by abnormalities in the left ventricle, associated valves, and ascending aorta. Studies have shown intrinsic myocardial defects but do not sufficiently explain developmental defects in the endocardial-derived cardiac valve, septum, and vasculature. Here, we identify a developmentally impaired endocardial population in HLHS through single-cell RNA profiling of hiPSC-derived endocardium and human fetal heart tissue with an underdeveloped left ventricle. Intrinsic endocardial defects contribute to abnormal endothelial-to-mesenchymal transition, NOTCH signaling, and extracellular matrix organization, key factors in valve formation. Endocardial abnormalities cause reduced cardiomyocyte proliferation and maturation by disrupting fibronectin-integrin signaling, consistent with recently described de novo HLHS mutations associated with abnormal endocardial gene and fibronectin regulation. Together, these results reveal a critical role for endocardium in HLHS etiology and provide a rationale for considering endocardial function in regenerative strategies.

Keywords: ETS1; NOTCH; de novo mutation; endocardium; endothelial to mesenchymal transition; fibronectin; human heart tissue; hypoplastic left heart syndrome; induced pluripotent stem cells; single-cell RNA-seq.

Publication types

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

MeSH terms

Endocardium
Humans
Hypoplastic Left Heart Syndrome*
Induced Pluripotent Stem Cells*
Myocardium
Signal Transduction

Abstract

Publication types

MeSH terms

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