Functional cardiac fibroblasts derived from human pluripotent stem cells via second heart field progenitors

Jianhua Zhang (), Ran Tao, Katherine F. Campbell, Juliana L. Carvalho, Edward C. Ruiz, Gina C. Kim, Eric G. Schmuck, Amish N. Raval, André Monteiro da Rocha, Todd J. Herron, José Jalife, James A. Thomson and Timothy J. Kamp ()
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Jianhua Zhang: University of Wisconsin-Madison
Ran Tao: University of Wisconsin-Madison
Katherine F. Campbell: Cardiovascular Medicine, University of Michigan
Juliana L. Carvalho: University of Wisconsin-Madison
Edward C. Ruiz: University of Wisconsin-Madison
Gina C. Kim: University of Wisconsin-Madison
Eric G. Schmuck: University of Wisconsin-Madison
Amish N. Raval: University of Wisconsin-Madison
André Monteiro da Rocha: Cardiovascular Medicine, University of Michigan
Todd J. Herron: Cardiovascular Medicine, University of Michigan
José Jalife: Cardiovascular Medicine, University of Michigan
James A. Thomson: Morgridge Institute for Research
Timothy J. Kamp: University of Wisconsin-Madison

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Cardiac fibroblasts (CFs) play critical roles in heart development, homeostasis, and disease. The limited availability of human CFs from native heart impedes investigations of CF biology and their role in disease. Human pluripotent stem cells (hPSCs) provide a highly renewable and genetically defined cell source, but efficient methods to generate CFs from hPSCs have not been described. Here, we show differentiation of hPSCs using sequential modulation of Wnt and FGF signaling to generate second heart field progenitors that efficiently give rise to hPSC-CFs. The hPSC-CFs resemble native heart CFs in cell morphology, proliferation, gene expression, fibroblast marker expression, production of extracellular matrix and myofibroblast transformation induced by TGFβ1 and angiotensin II. Furthermore, hPSC-CFs exhibit a more embryonic phenotype when compared to fetal and adult primary human CFs. Co-culture of hPSC-CFs with hPSC-derived cardiomyocytes distinctly alters the electrophysiological properties of the cardiomyocytes compared to co-culture with dermal fibroblasts. The hPSC-CFs provide a powerful cell source for research, drug discovery, precision medicine, and therapeutic applications in cardiac regeneration.

Date: 2019
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DOI: 10.1038/s41467-019-09831-5

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