Targeting TIMP1 with neutralizing antibodies reduced myofibroblast proliferation and fibrosis post-myocardial infarction in mice.
Does targeting TIMP1 with neutralizing antibodies reduce myofibroblast proliferation and fibrosis post-MI in mice?
The study identifies two distinct types of cardiac fibrosis ('hot' and 'cold') and demonstrates that targeting the myofibroblast autocrine growth factor loop via TIMP1 reduces cold fibrosis post-MI in mice.
Fibrosis remains a major unmet medical need. Simplifying principles are needed to better understand fibrosis and to yield new therapeutic approaches. Fibrosis is driven by myofibroblasts that interact with macrophages. A mathematical cell-circuit model predicts two types of fibrosis: hot fibrosis driven by macrophages and myofibroblasts and cold fibrosis driven by myofibroblasts alone. Testing these concepts in cardiac fibrosis resulting from myocardial infarction (MI) and heart failure (HF), we revealed that acute MI leads to cold fibrosis whereas chronic injury (HF) leads to hot fibrosis. MI-driven cold fibrosis is conserved in pigs and humans. We computationally identified a vulnerability of cold fibrosis: the myofibroblast autocrine growth factor loop. Inhibiting this loop by targeting TIMP1 with neutralizing antibodies reduced myofibroblast proliferation and fibrosis post-MI in mice. Our study demonstrates the utility of the concepts of hot and cold fibrosis and the feasibility of a circuit-to-target approach to pinpoint a treatment strategy that reduces fibrosis. A record of this paper's transparent peer review process is included in the supplemental information.
Miyara et al. (Tue,) conducted a other in Cardiac fibrosis. TIMP1 neutralizing antibodies was evaluated on Myofibroblast proliferation and fibrosis. Targeting TIMP1 with neutralizing antibodies reduced myofibroblast proliferation and fibrosis post-myocardial infarction in mice.