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

Autor:	Ong LP; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK. Electronic address: lpo20@cam.ac.uk., Bargehr J; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK., Knight-Schrijver VR; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK., Lee J; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK., Colzani M; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK., Bayraktar S; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK., Bernard WG; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK., Marchiano S; Departments of Laboratory Medicine & Pathology, Bioengineering, and Medicine/Cardiology, University of Washington, Seattle, WA, USA; Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA., Bertero A; Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy., Murry CE; Departments of Laboratory Medicine & Pathology, Bioengineering, and Medicine/Cardiology, University of Washington, Seattle, WA, USA; Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA., Gambardella L; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK., Sinha S; Wellcome - MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Puddicombe Way, CB2 0AW Cambridge, UK; Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, ACCI Level 6, Hills Road, Box 110, Cambridge CB2 0QQ, UK. Electronic address: ss661@cam.ac.uk.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2023 Apr 11; Vol. 18 (4), pp. 936-951. Date of Electronic Publication: 2023 Mar 30.
DOI:	10.1016/j.stemcr.2023.03.002
Abstrakt:	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 Ca 2+ 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. Competing Interests: Conflict of interests S.S. and J.B. are co-founders and shareholders in ABS Biotechnologies GmbH. (Copyright © 2023. Published by Elsevier Inc.)
Databáze:	MEDLINE
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