دورية أكاديمية
Perlecan (HSPG2) promotes structural, contractile, and metabolic development of human cardiomyocytes.
| العنوان: | Perlecan (HSPG2) promotes structural, contractile, and metabolic development of human cardiomyocytes. |
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| المؤلفون: | Johnson BB; Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK., Cosson MV; The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK., Tsansizi LI; The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK., Holmes TL; Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK., Gilmore T; The Francis Crick Institute, London NW1 1AT, UK., Hampton K; Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK., Song OR; The Francis Crick Institute, London NW1 1AT, UK; High-Throughput Screening Science Technology Platform, The Francis Crick Institute, London NW1 1AT, UK., Vo NTN; School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK., Nasir A; School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK., Chabronova A; Institute of Life Course and Medical Sciences, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK., Denning C; School of Medicine, Regenerating and Modelling Tissues, Biodiscovery Institute, University Park, University of Nottingham, Nottingham NG7 2RD, UK., Peffers MJ; Institute of Life Course and Medical Sciences, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK., Merry CLR; 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., Whitelock J; 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., Troeberg L; Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK., Rushworth SA; Centre for Metabolic Health, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, UK., Bernardo AS; The Francis Crick Institute, London NW1 1AT, UK; NHLI, Imperial College London, London, UK. Electronic address: a.bernardo@imperial.ac.uk., Smith JGW; 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. |
| المصدر: | Cell reports [Cell Rep] 2024 Jan 23; Vol. 43 (1), pp. 113668. Date of Electronic Publication: 2024 Jan 09. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Cambridge, MA] : Cell Press, c 2012- |
| مواضيع طبية MeSH: | Heparan Sulfate Proteoglycans*/genetics , Heparan Sulfate Proteoglycans*/metabolism , Agrin*/metabolism, Humans ; Myocytes, Cardiac/metabolism ; Extracellular Matrix/metabolism ; Extracellular Matrix Proteins/metabolism |
| مستخلص: | 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. Competing Interests: Declaration of interests A patent application related to the left ventricle CM differentiation protocol used in this work has been submitted (WO 2020/245612) and is partly licensed to Axol Biosciences. A.S.B. is a beneficiary of this license. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| معلومات مُعتمدة: | NC/T2T0119 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; FS/12/37/29516 United Kingdom BHF_ British Heart Foundation; SP/15/9/31605 United Kingdom BHF_ British Heart Foundation; PG/21/10545 United Kingdom BHF_ British Heart Foundation; NC/C013202/1 United Kingdom NC3RS_ National Centre for the Replacement, Refinement and Reduction of Animals in Research; 210987/Z/18/Z United Kingdom WT_ Wellcome Trust |
| فهرسة مساهمة: | 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 |
| المشرفين على المادة: | 143972-95-6 (perlecan) 0 (Heparan Sulfate Proteoglycans) 0 (Agrin) 0 (Extracellular Matrix Proteins) |
| تواريخ الأحداث: | Date Created: 20240110 Date Completed: 20240126 Latest Revision: 20240320 |
| رمز التحديث: | 20240320 |
| DOI: | 10.1016/j.celrep.2023.113668 |
| PMID: | 38198277 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2211-1247 |
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| DOI: | 10.1016/j.celrep.2023.113668 |