Perlecan (HSPG2) promotes structural, contractile, and metabolic development of human cardiomyocytes

Johnson, Benjamin B., Cosson, Marie-Victoire, Tsansizi, Lorenza I., Holmes, Terri L., Gilmore, Tegan, Hampton, Katherine, Song, Ok-Ryul, Vo, Nguyen T. N., Nasir, Aishah, Chabronova, Alzbeta, Denning, Chris, Peffers, Mandy J., Merry, Catherine L. R., Whitelock, John, Troeberg, Linda ORCID: https://orcid.org/0000-0003-0939-4651, Rushworth, Stuart A., Bernardo, Andreia S. and Smith, James G. W. ORCID: https://orcid.org/0000-0003-0427-8678 (2024) Perlecan (HSPG2) promotes structural, contractile, and metabolic development of human cardiomyocytes. Cell Reports, 43 (1). ISSN 2211-1247

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Abstract

Perlecan (HSPG2), a heparan sulfate proteoglycan similar to agrin, is key for extracellular matrix (ECM) maturation and stabilization. Although crucial for cardiac development, its role remains elusive. We show that perlecan expression increases as cardiomyocytes mature in vivo and during human pluripotent stem cell differentiation to cardiomyocytes (hPSC-CMs). Perlecan-haploinsuffient hPSCs (HSPG2+/−) differentiate efficiently, but late-stage CMs have structural, contractile, metabolic, and ECM gene dysregulation. In keeping with this, late-stage HSPG2+/− hPSC-CMs have immature features, including reduced ⍺-actinin expression and increased glycolytic metabolism and proliferation. Moreover, perlecan-haploinsuffient engineered heart tissues have reduced tissue thickness and force generation. Conversely, hPSC-CMs grown on a perlecan-peptide substrate are enlarged and display increased nucleation, typical of hypertrophic growth. Together, perlecan appears to play the opposite role of agrin, promoting cellular maturation rather than hyperplasia and proliferation. Perlecan signaling is likely mediated via its binding to the dystroglycan complex. Targeting perlecan-dependent signaling may help reverse the phenotypic switch common to heart failure.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Biological Sciences Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
Depositing User:	LivePure Connector
Date Deposited:	13 Jan 2024 01:37
Last Modified:	13 Jan 2024 01:38
URI:	https://ueaeprints.uea.ac.uk/id/eprint/94170
DOI:	10.1016/j.celrep.2023.113668

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