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

Johnson, Benjamin B. (author)
Univ East Anglia, Ctr Metab Hlth, Norwich Med Sch, Norwich Res Pk, Norwich NR4 7UQ, England.
Cosson, Marie-Victoire (author)
Francis Crick Inst, London NW1 1AT, England.;Imperial Coll London, NHLI, London, England.
Tsansizi, Lorenza I. (author)
Francis Crick Inst, London NW1 1AT, England.;Imperial Coll London, NHLI, London, England.
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Holmes, Terri L. (author)
Univ East Anglia, Ctr Metab Hlth, Norwich Med Sch, Norwich Res Pk, Norwich NR4 7UQ, England.
Gilmore, Tegan (author)
Francis Crick Inst, London NW1 1AT, England.
Hampton, Katherine (author)
Univ East Anglia, Ctr Metab Hlth, Norwich Med Sch, Norwich Res Pk, Norwich NR4 7UQ, England.
Song, Ok-Ryul (author)
Francis Crick Inst, London NW1 1AT, England.;Francis Crick Inst, High Throughput Screening Sci Technol Platform, London NW1 1AT, England.
Vo, Nguyen T. N. (author)
Univ Nottingham, Biodiscovery Inst, Sch Med Regenerating & Modelling Tissues, Univ Pk, Nottingham NG7 2RD, England.
Nasir, Aishah (author)
Univ Nottingham, Biodiscovery Inst, Sch Med Regenerating & Modelling Tissues, Univ Pk, Nottingham NG7 2RD, England.
Chabronova, Alzbeta (author)
Inst Life Course & Med Sci, William Henry Duncan Bldg,6 West Derby St, Liverpool L7 8TX, England.
Denning, Chris (author)
Univ Nottingham, Biodiscovery Inst, Sch Med Regenerating & Modelling Tissues, Univ Pk, Nottingham NG7 2RD, England.
Peffers, Mandy J. (author)
Inst Life Course & Med Sci, William Henry Duncan Bldg,6 West Derby St, Liverpool L7 8TX, England.
Merry, Catherine L. R. (author)
Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Univ Nottingham, Biodiscovery Inst, Sch Med Regenerating & Modelling Tissues, Univ Pk, Nottingham NG7 2RD, England.
Whitelock, John (author)
Univ Nottingham, Biodiscovery Inst, Sch Med Regenerating & Modelling Tissues, Univ Pk, Nottingham NG7 2RD, England.;Univ New South Wales, Grad Sch Biomed Engn, Sydney, NSW 2052, Australia.
Troeberg, Linda (author)
Univ East Anglia, Ctr Metab Hlth, Norwich Med Sch, Norwich Res Pk, Norwich NR4 7UQ, England.
Rushworth, Stuart A. (author)
Univ East Anglia, Ctr Metab Hlth, Norwich Med Sch, Norwich Res Pk, Norwich NR4 7UQ, England.
Bernardo, Andreia S. (author)
Francis Crick Inst, London NW1 1AT, England.;Imperial Coll London, NHLI, London, England.
Smith, James G. W. (author)
Univ East Anglia, Ctr Metab Hlth, Norwich Med Sch, Norwich Res Pk, Norwich NR4 7UQ, England.
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Univ East Anglia, Ctr Metab Hlth, Norwich Med Sch, Norwich Res Pk, Norwich NR4 7UQ, England Francis Crick Inst, London NW1 1AT, England.;Imperial Coll London, NHLI, London, England. (creator_code:org_t)
Elsevier, 2024
2024
English.
In: Cell Reports. - : Elsevier. - 2211-1247. ; 43:1
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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 alpha-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 perlecanpeptide 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

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