Modeling human multi-lineage heart field development with pluripotent stem cells

Donghe Yang; Juliana Gomez-Garcia; Shunsuke Funakoshi; Thinh Tran; Ian Fernandes; Gary D Bader; Michael A Laflamme; Gordon M Keller

doi:10.1016/j.stem.2022.08.007

Modeling human multi-lineage heart field development with pluripotent stem cells

Cell Stem Cell. 2022 Sep 1;29(9):1382-1401.e8. doi: 10.1016/j.stem.2022.08.007.

Authors

Donghe Yang¹, Juliana Gomez-Garcia², Shunsuke Funakoshi³, Thinh Tran⁴, Ian Fernandes⁵, Gary D Bader⁶, Michael A Laflamme⁷, Gordon M Keller⁸

Affiliations

¹ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: donghe.yang@mail.utoronto.ca.
² McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Biomedical Engineering, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁵ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁶ Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁷ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁸ McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: gordon.keller@uhnresearch.ca.

PMID: 36055193
DOI: 10.1016/j.stem.2022.08.007

Abstract

The cardiomyocyte (CM) subtypes in the mammalian heart derive from distinct lineages known as the first heart field (FHF), the anterior second heart field (aSHF), and the posterior second heart field (pSHF) lineages that are specified during gastrulation. We modeled human heart field development from human pluripotent stem cells (hPSCs) by using single-cell RNA-sequencing to delineate lineage specification and progression. Analyses of hPSC-derived and mouse mesoderm transcriptomes enabled the identification of distinct human FHF, aSHF, and pSHF mesoderm subpopulations. Through staged manipulation of signaling pathways identified from transcriptomics, we generated myocyte populations that display molecular characteristics of key CM subtypes. The developmental trajectory of the human cardiac lineages recapitulated that of the mouse, demonstrating conserved cardiovascular programs. These findings establish a comprehensive landscape of human embryonic cardiogenesis that provides access to a broad spectrum of cardiomyocytes for modeling congenital heart diseases and chamber-specific cardiomyopathies as well as for developing new therapies to treat them.

Keywords: cardiac mesoderm specification; cardiomyocyte subtypes; hPSC models; human and mouse comparison; human heart field development; scRNA-seq.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Embryo, Mammalian
Humans
Mammals
Mesoderm
Mice
Myocytes, Cardiac / metabolism
Pluripotent Stem Cells* / metabolism

Grants and funding

FDN159937/CIHR/Canada