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

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

Free article

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

Donghe Yang et al. Cell Stem Cell. 2022.

Free article

. 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.

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Conflict of interest statement

Declaration of interests G.M.K. is a scientific founder and paid consultant for BlueRock Therapeutics, LP, a paid consultant for VistaGen Therapeutics, and a board member of Anagenesis Biotechnologies. M.A.L. is a paid consultant for BlueRock Therapeutics, LP. G.M.K. and D.Y. declare a patent titled “Cardiomyocyte subtypes and methods of making and using” (no. PCT/IB2022/055,425) related to this work.

Comment in

Uncovering the origins and lineage markers of human heart fields.
Miyamoto M, Kwon C. Miyamoto M, et al. Cell Stem Cell. 2022 Sep 1;29(9):1285-1287. doi: 10.1016/j.stem.2022.08.004. Cell Stem Cell. 2022. PMID: 36055186 Free PMC article.

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

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases