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

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-deriv...

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Bibliographic Details
Published in:Stem cell reports 2023-04, Vol.18 (4), p.936-951
Main Authors: Ong, Lay Ping, Bargehr, Johannes, Knight-Schrijver, Vincent R., Lee, Jonathan, Colzani, Maria, Bayraktar, Semih, Bernard, William G., Marchiano, Silvia, Bertero, Alessandro, Murry, Charles E., Gambardella, Laure, Sinha, Sanjay
Format: Article
Language:English
Subjects:
cardiomyocytes
Cell Differentiation - genetics
engineered heart tissues
epicardium
fibronectin
Fibronectins
Humans
Induced Pluripotent Stem Cells
maturation
Myocytes, Cardiac
Pluripotent Stem Cells
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Summary: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. [Display omitted] •Loss of epicardial fibronectin led to immature stem cell-derived cardiomyocytes in 3D-EHTs•Adding recombinant fibronectin recovered the maturation effect of epicardium in 3D-EHTs•Fibronectin is part of the epicardial-cardiomyocyte crosstalk driving myocardial maturation•Epicardial-cardiomyocyte interactome shows key signaling pathways in cardiac development The corresponding author and colleagues demonstrated that epicardially secreted fibronectin augmented cardiomyocyte maturation in 3D-engineered heart tissues and provided a genetic map of the key regulatory pathways governing epicardial-myocardial crosstalk. As the epicardium is crucial for cardiac development and cardiomyocyte maturation, these findings will affect future work on stem-cell-based cardiac tissue engineering.
ISSN:2213-6711
2213-6711
DOI:10.1016/j.stemcr.2023.03.002