Consequences of PDGFRα+ fibroblast reduction in adult murine hearts
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Updated: Aug 27, 2025
Isolation and Characterization of Adult Cardiac Fibroblasts and Myofibroblasts
Published on: March 12, 2020
Jill T Kuwabara1,2, Akitoshi Hara1, Sumit Bhutada3
1Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United States.
Insights
Reducing cardiac fibroblasts in mice improved heart function after injury, suggesting potential therapeutic benefits for heart disease. This study explored fibroblast roles in cardiac fibrosis and repair.
Area of Science:
- Cardiovascular Biology
- Extracellular Matrix Research
- Fibrosis and Cardiac Remodeling
Background:
- Cardiac fibroblasts are key producers of collagen and regulators of the extracellular matrix (ECM).
- The precise role of fibroblasts in maintaining cardiac ECM homeostasis and their contribution to pathological fibrosis remain unclear.
- Understanding fibroblast function is crucial for developing therapies for heart disease.
Purpose of the Study:
- To investigate the impact of fibroblast ablation on adult mouse heart ECM homeostasis and cardiac function post-injury.
- To elucidate the role of fibroblasts in cardiac fibrosis and their response to injury.
- To assess the potential therapeutic value of controlled fibroblast reduction in heart disease.
Main Methods:
- Genetic ablation of fibroblasts in adult mice.
- Quantitative mass spectrometry and N-terminomics to analyze ECM proteome.
- Assessment of cardiac function using models of angiotensin II/phenylephrine-induced fibrosis and myocardial infarction (MI).
- Analysis of cardiomyocyte function, including sarcomere shortening and calcium handling.
Main Results:
- Fibroblast ablation led to reduced cardiac fibroblast numbers but did not overtly alter overall fibrillar collagen or the ECM proteome.
- A significant reduction in collagen VI, a microfibrillar collagen, was observed.
- Fibroblast-ablated mice exhibited preserved cardiac function following induced fibrosis and myocardial infarction.
- Cardiomyocyte function showed altered sarcomere shortening and slower calcium decline.
- Residual fibroblasts responded to injury, but with diminished proliferation and numbers.
Conclusions:
- The adult mouse heart can tolerate substantial fibroblast loss, which may beneficially impact cardiac function after injury.
- Controlled reduction of cardiac fibroblasts demonstrates cardioprotective effects, indicating potential therapeutic applications for heart disease.
- Fibroblasts play a complex role in cardiac injury response, and their modulation could be a viable therapeutic strategy.
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, 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 a potentially beneficial impact on cardiac function after injury. The cardioprotective effect of controlled fibroblast reduction may have therapeutic value in heart disease.
