Consequences of PDGFR a + fibroblast reduction in adult murine hearts
- University of Hawaii at Manoa, United States
- Cleveland Clinic Lerner Research Institute, United States
- The Ohio State University Wexner Medical Center, United States
Abstract
Fibroblasts produce the majority of collagen in the heart and are thought to regulate extracellular matrix (ECM) turnover. Although fibrosis accompanies many cardiac pathologies and is generally deleterious, the role of fibroblasts in maintaining the basal ECM network and in fibrosis in vivo is poorly understood. We genetically ablated fibroblasts in mice to evaluate the impact on homeostasis of adult ECM and cardiac function after injury. Fibroblast-ablated mice demonstrated a substantive reduction in cardiac fibroblasts, but fibrillar collagen and the ECM proteome were not overtly altered when evaluated by quantitative mass spectrometry and N-terminomics. However, the distribution and quantity of collagen VI, a microfibrillar collagen that forms an open network with the basement membrane, was reduced. In fibroblast-ablated mice, cardiac function was better preserved following angiotensin II/phenylephrine (AngII/PE)-induced fibrosis and myocardial infarction (MI). Analysis of cardiomyocyte function demonstrated altered sarcomere shortening and slowed calcium decline in both uninjured and AngII/PE infused fibroblast-ablated mice. After MI, the residual resident fibroblasts responded to injury, albeit with reduced proliferation and numbers immediately after injury. These results indicate that the adult mouse heart tolerates a significant degree of fibroblast loss with potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.
Data availability
Mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD021741 (shotgun proteomics) and PXD021739 (N-terminomics).
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Consequences of fibroblast ablation in adult murine heartsProteomeXchange Consortium, PXD021739.
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Consequences of fibroblast ablation in adult murine heartsProteomeXchange Consortium, PXD021741.
Article and author information
Author details
Michelle D Tallquist
Funding
National Institutes of Health (HL074257)
- Michelle D Tallquist
National Institutes of Health (HL115505)
- Jill T Kuwabara
American Heart Association (PRE29630019)
- Jill T Kuwabara
American Heart Association (GRNT33660474)
- Michelle D Tallquist
American Heart Association (PRE834732)
- Jasmine Chen
American Heart Association
- Suneel S Apte
Paul G. Allen Frontiers Group
- Suneel S Apte
Japan Society for the Promotion of Science
- Akitoshi Hara
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Christopher L-H Huang, University of Cambridge, United Kingdom
Ethics
Animal experimentation: All mouse experiments were performed according to the animal experimental guidelines issued and approved by Institutional Animal Care and Use Committees of the University of Hawaii at Manoa (APN12-1421 and APN12-1469) and The Ohio State University Wexner Medical Center (#2021A00000070). All surgeries were performed under isofluorane anesthesia, and every effort was made to minimize suffering.
Version history
- Received: April 28, 2021
- Preprint posted: May 8, 2021 (view preprint)
- Accepted: September 22, 2022
- Accepted Manuscript published: September 23, 2022 (version 1)
- Version of Record published: October 17, 2022 (version 2)
Copyright
© 2022, Kuwabara et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Consequences of PDGFR a + fibroblast reduction in adult murine hearts
eLife 11:e69854.
https://doi.org/10.7554/eLife.69854
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