Cold and hot fibrosis define clinically distinct cardiac pathologies

Area of Science:

• Cell biology
• Immunology
• Cardiovascular research

Background:

• Fibrosis, a significant unmet medical need, involves complex cellular interactions.
• Understanding the drivers of fibrosis is crucial for developing new therapies.
• Myofibroblasts and macrophages are key cellular players in fibrotic processes.

Purpose of the Study:

• To introduce and validate a mathematical model distinguishing "hot" and "cold" fibrosis.
• To investigate the distinct fibrotic responses in acute myocardial infarction (MI) and chronic heart failure (HF).
• To identify and test therapeutic targets for fibrosis reduction.

Main Methods:

• Development of a mathematical cell-circuit model to define fibrosis types.
• Analysis of cardiac fibrosis in mouse models of acute MI and chronic HF.
• Computational identification of myofibroblast autocrine signaling vulnerabilities.
• In vivo testing of TIMP1-neutralizing antibodies in a mouse model.

Main Results:

• The model predicted two fibrosis types: "hot" (macrophage and myofibroblast driven) and "cold" (myofibroblast driven).
• Acute MI induced "cold" fibrosis, while chronic HF led to "hot" fibrosis, consistent across species.
• Targeting the myofibroblast autocrine growth factor loop via TIMP1 inhibition reduced fibrosis post-MI in mice.

Conclusions:

• The concepts of "hot" and "cold" fibrosis provide a new framework for understanding fibrotic diseases.
• A circuit-to-target approach is feasible for identifying novel anti-fibrotic strategies.
• TIMP1 inhibition represents a potential therapeutic strategy for reducing fibrosis, particularly in post-MI settings.