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Epicardially secreted fibronectin drives cardiomyocyte maturation in 3D-engineered heart tissues.

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Ong, Lay Ping 
Bargehr, Johannes 
Knight-Schrijver, Vincent R 
Lee, Jonathan 
Colzani, Maria 

Abstract

Ischemic heart failure is due to irreversible loss of cardiomyocytes. Preclinical studies showed that human pluripotent stem cell (hPSC)-derived cardiomyocytes could remuscularize infarcted hearts and improve cardiac function. However, these cardiomyocytes remained immature. Incorporating hPSC-derived epicardial cells has been shown to improve cardiomyocyte maturation, but the exact mechanisms are unknown. We posited epicardial fibronectin (FN1) as a mediator of epicardial-cardiomyocyte crosstalk and assessed its role in driving hPSC-derived cardiomyocyte maturation in 3D-engineered heart tissues (3D-EHTs). We found that the loss of FN1 with peptide inhibition F(pUR4), CRISPR-Cas9-mediated FN1 knockout, or tetracycline-inducible FN1 knockdown in 3D-EHTs resulted in immature cardiomyocytes with decreased contractile function, and inefficient Ca2+ handling. Conversely, when we supplemented 3D-EHTs with recombinant human FN1, we could recover hPSC-derived cardiomyocyte maturation. Finally, our RNA-sequencing analyses found FN1 within a wider paracrine network of epicardial-cardiomyocyte crosstalk, thus solidifying FN1 as a key driver of hPSC-derived cardiomyocyte maturation in 3D-EHTs.

Description

Keywords

cardiomyocytes, engineered heart tissues, epicardium, fibronectin, maturation, Humans, Myocytes, Cardiac, Fibronectins, Cell Differentiation, Pluripotent Stem Cells, Induced Pluripotent Stem Cells

Journal Title

Stem Cell Reports

Conference Name

Journal ISSN

2213-6711
2213-6711

Volume Title

18

Publisher

Elsevier BV
Sponsorship
British Heart Foundation (SP/15/7/31561)
Wellcome Trust (203568/Z/16/Z)
Wellcome Trust (203151/Z/16/Z)
British Heart Foundation (FS/18/46/33663)
Medical Research Council (MC_PC_17230)

Version History

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2*
2023-12-07 18:36:53
Published version added
2023-04-12 23:30:59
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