Back to Search
Start Over
Perlecan (HSPG2) promotes structural, contractile, and metabolic development of human cardiomyocytes.
- Source :
-
Cell reports [Cell Rep] 2024 Jan 23; Vol. 43 (1), pp. 113668. Date of Electronic Publication: 2024 Jan 09. - Publication Year :
- 2024
-
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 <superscript>+/-</superscript> ) differentiate efficiently, but late-stage CMs have structural, contractile, metabolic, and ECM gene dysregulation. In keeping with this, late-stage HSPG2 <superscript>+/-</superscript> 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.<br />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.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 43
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 38198277
- Full Text :
- https://doi.org/10.1016/j.celrep.2023.113668