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Updated: May 21, 2025
Scanning Electron Microscopy of Macerated Tissue to Visualize the Extracellular Matrix
Published on: June 14, 2016
Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis
Sangkyun Cho1,2, Siyeon Rhee3,4,5, Christopher M Madl6,7
1Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. sangcho@stanford.edu.
Insights
Inhibiting matrix mechanosensing and TGFβ signaling in cardiac fibroblasts can suppress cardiovascular fibrosis. Targeting SRC kinase and TGFβ pathway shows promise for treating heart failure.
Area of Science:
- Cardiovascular Biology
- Fibrosis Research
- Mechanobiology
Background:
- Biophysical cues from the extracellular matrix regulate fibroblast activation and myofibroblast differentiation.
- The role of matrix mechanosensing in suppressing cardiovascular fibrosis is not fully understood.
Purpose of the Study:
- To investigate if modulating matrix mechanosensing signals can suppress cardiovascular fibrosis.
- To identify key mechanosensors in cardiac fibroblasts and evaluate therapeutic targets.
Main Methods:
- Meta-analysis of single-cell sequencing datasets to identify fibroblast mechanosensors.
- Pharmacological inhibition of SRC kinase (using saracatinib) and TGFβ pathway.
- Assessment of transcriptomic, morphological, and metabolic shifts in fibroblasts.
- Evaluation of contractile function in engineered heart tissues and a mouse model of heart failure.
Main Results:
- SRC, a focal-adhesion-associated tyrosine kinase, was identified as a fibroblast-enriched mechanosensor.
- Dual inhibition of SRC and TGFβ synergistically repressed profibrotic gene programs by inhibiting the MRTF-SRF pathway.
- Combined treatment alleviated contractile dysfunction in fibrotic heart tissues and a mouse model of heart failure.
Conclusions:
- Targeting SRC-mediated stromal mechanosensing alongside TGFβ signaling offers a potential therapeutic strategy for cardiovascular fibrosis.
- This dual inhibition promotes a shift towards fibroblast quiescence, mitigating fibrosis and improving cardiac function.
Abstract:
Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1-6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7-10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.
