Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury

Tomohiro Yokota; Jackie McCourt; Feiyang Ma; Shuxun Ren; Shen Li; Tae-Hyung Kim; Yerbol Z Kurmangaliyev; Rohollah Nasiri; Samad Ahadian; Thang Nguyen; Xing Haw Marvin Tan; Yonggang Zhou; Rimao Wu; Abraham Rodriguez; Whitaker Cohn; Yibin Wang; Julian Whitelegge; Sergey Ryazantsev; Ali Khademhosseini; Michael A Teitell; Pei-Yu Chiou; David E Birk; Amy C Rowat; Rachelle H Crosbie; Matteo Pellegrini; Marcus Seldin; Aldons J Lusis; Arjun Deb

doi:10.1016/j.cell.2020.06.030

Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury

Cell. 2020 Aug 6;182(3):545-562.e23. doi: 10.1016/j.cell.2020.06.030. Epub 2020 Jul 3.

Authors

Tomohiro Yokota¹, Jackie McCourt², Feiyang Ma³, Shuxun Ren⁴, Shen Li¹, Tae-Hyung Kim², Yerbol Z Kurmangaliyev⁵, Rohollah Nasiri⁶, Samad Ahadian⁷, Thang Nguyen⁸, Xing Haw Marvin Tan⁹, Yonggang Zhou¹, Rimao Wu¹, Abraham Rodriguez¹, Whitaker Cohn¹⁰, Yibin Wang⁴, Julian Whitelegge¹⁰, Sergey Ryazantsev¹¹, Ali Khademhosseini¹², Michael A Teitell¹³, Pei-Yu Chiou⁹, David E Birk¹⁴, Amy C Rowat¹⁵, Rachelle H Crosbie¹⁶, Matteo Pellegrini³, Marcus Seldin¹⁷, Aldons J Lusis¹⁸, Arjun Deb¹⁹

Affiliations

¹ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA.
² Department of Integrative Biology and Physiology, University of California, CA 90095, USA.
³ Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
⁴ Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Biological Chemistry, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
⁶ California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA; Department of Bioengineering, School of Engineering, University of California, Los Angeles, CA 90095, USA; Department of Mechanical Engineering, Sharif University of Technology, Tehran 11365-11155, Iran.
⁷ California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA; Department of Bioengineering, School of Engineering, University of California, Los Angeles, CA 90095, USA; Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA 90024, USA.
⁸ Department of Bioengineering, School of Engineering, University of California, Los Angeles, CA 90095, USA.
⁹ California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA; Department of Bioengineering, School of Engineering, University of California, Los Angeles, CA 90095, USA; Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, CA 90095, USA.
¹⁰ Passarow Mass Spectrometry Laboratory, Semel Institute for Neuroscience and Behaviour, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
¹¹ California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA.
¹² California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA; Department of Bioengineering, School of Engineering, University of California, Los Angeles, CA 90095, USA; Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA 90024, USA; Department of Chemical Engineering, School of Engineering, University of California, Los Angeles, CA 90095, USA; Department of Radiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
¹³ Department of Bioengineering, School of Engineering, University of California, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
¹⁴ University of South Florida College of Medicine, Tampa, FL 33612, USA.
¹⁵ Department of Integrative Biology and Physiology, University of California, CA 90095, USA; Department of Bioengineering, School of Engineering, University of California, Los Angeles, CA 90095, USA.
¹⁶ Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; Department of Integrative Biology and Physiology, University of California, CA 90095, USA.
¹⁷ Department of Biological Chemistry and Center for Epigenetics and Metabolism, University of California, Irvine, CA 92697, USA.
¹⁸ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Genetics, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
¹⁹ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California, Los Angeles, CA 90095, USA; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA; California Nanosystems Institute, University of California, Los Angeles, CA 90095, USA. Electronic address: adeb@mednet.ucla.edu.

Abstract

Scar tissue size following myocardial infarction is an independent predictor of cardiovascular outcomes, yet little is known about factors regulating scar size. We demonstrate that collagen V, a minor constituent of heart scars, regulates the size of heart scars after ischemic injury. Depletion of collagen V led to a paradoxical increase in post-infarction scar size with worsening of heart function. A systems genetics approach across 100 in-bred strains of mice demonstrated that collagen V is a critical driver of postinjury heart function. We show that collagen V deficiency alters the mechanical properties of scar tissue, and altered reciprocal feedback between matrix and cells induces expression of mechanosensitive integrins that drive fibroblast activation and increase scar size. Cilengitide, an inhibitor of specific integrins, rescues the phenotype of increased post-injury scarring in collagen-V-deficient mice. These observations demonstrate that collagen V regulates scar size in an integrin-dependent manner.

Keywords: Col5a1; cilengitide; collagen V; fibrosis; heart scar; integrins; scar mechanics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cicatrix / genetics
Cicatrix / metabolism*
Cicatrix / physiopathology
Collagen Type I / genetics
Collagen Type I / metabolism
Collagen Type I, alpha 1 Chain
Collagen Type III / genetics
Collagen Type III / metabolism
Collagen Type V / deficiency*
Collagen Type V / genetics
Collagen Type V / metabolism*
Extracellular Matrix / genetics
Extracellular Matrix / metabolism
Female
Fibrosis / genetics
Fibrosis / metabolism
Gene Expression Regulation / genetics
Heart Injuries / metabolism*
Integrins / antagonists & inhibitors
Integrins / genetics
Integrins / metabolism
Isoproterenol / pharmacology
Male
Mechanotransduction, Cellular / genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Microscopy, Atomic Force / instrumentation
Microscopy, Electron, Transmission
Myocardial Contraction / drug effects
Myocardial Contraction / genetics*
Myofibroblasts / cytology
Myofibroblasts / metabolism*
Myofibroblasts / pathology
Myofibroblasts / ultrastructure
Principal Component Analysis
Proteomics
RNA-Seq
Single-Cell Analysis

Substances

COL3A1 protein, mouse
Collagen Type I
Collagen Type I, alpha 1 Chain
Collagen Type III
Collagen Type V
Integrins
Isoproterenol

Abstract

Publication types

MeSH terms

Substances

Grants and funding