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.
Tomohiro Yokota  1 ,  Jackie McCourt  2 ,  Feiyang Ma  3 ,  Shuxun Ren  4 ,  Shen Li  1 ,  Tae-Hyung Kim  2 ,  Yerbol Z Kurmangaliyev  5 ,  Rohollah Nasiri  6 ,  Samad Ahadian  7 ,  Thang Nguyen  8 ,  Xing Haw Marvin Tan  9 ,  Yonggang Zhou  1 ,  Rimao Wu  1 ,  Abraham Rodriguez  1 ,  Whitaker Cohn  10 ,  Yibin Wang  4 ,  Julian Whitelegge  10 ,  Sergey Ryazantsev  11 ,  Ali Khademhosseini  12 ,  Michael A Teitell  13 ,  Pei-Yu Chiou  9 ,  David E Birk  14 ,  Amy C Rowat  15 ,  Rachelle H Crosbie  16 ,  Matteo Pellegrini  3 ,  Marcus Seldin  17 ,  Aldons J Lusis  18 ,  Arjun Deb  19
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: [email protected].
PMID: 32621799 DOI: 10.1016/j.cell.2020.06.030
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.
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