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

Benjamin B Johnson; Marie-Victoire Cosson; Lorenza I Tsansizi; Terri L Holmes; Tegan Gilmore; Katherine Hampton; Ok-Ryul Song; Nguyen T N Vo; Aishah Nasir; Alzbeta Chabronova; Chris Denning; Mandy J Peffers; Catherine L R Merry; John Whitelock; Linda Troeberg; Stuart A Rushworth; Andreia S Bernardo; James G W Smith

doi:10.1016/j.celrep.2023.113668

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

Cell Rep. 2024 Jan 23;43(1):113668. doi: 10.1016/j.celrep.2023.113668. Epub 2024 Jan 9.

Authors

Benjamin B Johnson¹, Marie-Victoire Cosson², Lorenza I Tsansizi², Terri L Holmes¹, Tegan Gilmore³, Katherine Hampton¹, Ok-Ryul Song⁴, Nguyen T N Vo⁵, Aishah Nasir⁵, Alzbeta Chabronova⁶, Chris Denning⁵, Mandy J Peffers⁶, Catherine L R Merry⁷, John Whitelock⁸, Linda Troeberg¹, Stuart A Rushworth¹, Andreia S Bernardo⁹, James G W Smith¹⁰

Affiliations

¹ Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK.
² The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK.
³ The Francis Crick Institute, London NW1 1AT, UK.
⁴ The Francis Crick Institute, London NW1 1AT, UK; High-Throughput Screening Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK.
⁵ School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK.
⁶ Institute of Life Course and Medical Sciences, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK.
⁷ School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK; Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
⁸ School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK; Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia.
⁹ The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK. Electronic address: a.bernardo@imperial.ac.uk.
¹⁰ Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK. Electronic address: j.g.smith@uea.ac.uk.

PMID: 38198277
DOI: 10.1016/j.celrep.2023.113668

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.

Keywords: CP: Cell biology; CP: Developmental biology; agrin; cardiac maturation; cardiomyocytes; extracellular matrix; heparan sulfate proteoglycan; human pluripotent stem cells; hypertrophy; multinucleation; perlecan; perlecan mutation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agrin* / metabolism
Extracellular Matrix / metabolism
Extracellular Matrix Proteins / metabolism
Heparan Sulfate Proteoglycans* / genetics
Heparan Sulfate Proteoglycans* / metabolism
Humans
Myocytes, Cardiac / metabolism

Substances

perlecan
Heparan Sulfate Proteoglycans
Agrin
Extracellular Matrix Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding