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
Affiliations
Benjamin B. Johnson
Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
Marie-Victoire Cosson
The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK
Lorenza I. Tsansizi
The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK
Terri L. Holmes
Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
Tegan Gilmore
The Francis Crick Institute, London NW1 1AT, UK
Katherine Hampton
Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
Ok-Ryul Song
The Francis Crick Institute, London NW1 1AT, UK; High-Throughput Screening Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK
Nguyen T.N. Vo
School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK
Aishah Nasir
School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK
Alzbeta Chabronova
Institute of Life Course and Medical Sciences, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
Chris Denning
School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK
Mandy J. Peffers
Institute of Life Course and Medical Sciences, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK
Catherine L.R. Merry
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
John Whitelock
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
Linda Troeberg
Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
Stuart A. Rushworth
Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK
Andreia S. Bernardo
The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK; Corresponding author
James G.W. Smith
Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK; Corresponding author
Summary: 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.
