Cold and hot fibrosis define clinically distinct cardiac pathologies
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.
Authors
- Ofra Golani (ORCID: https://orcid.org/0000-0002-9793-236X)
- Julio Sáez-Rodríguez (ORCID: https://orcid.org/0000-0002-8552-8976)
- Shoval Miyara (ORCID: https://orcid.org/0000-0002-9003-046X)
- Michael Gershovits
- Miri Adler (ORCID: https://orcid.org/0000-0003-4687-7572)
- Tatjana Dorn
- Tali Shalit (ORCID: https://orcid.org/0009-0005-2651-1591)
- Daria Lendengolts
- Yalin Divinsky (ORCID: https://orcid.org/0000-0001-5275-4312)
- Ricardo O. Ramirez Flores (ORCID: https://orcid.org/0000-0003-0087-371X)
- Elly M. Tanaka (ORCID: https://orcid.org/0000-0003-4240-2158)
- Jingkui Wang (ORCID: https://orcid.org/0000-0002-0127-501X)
- Ruslan M. Medzhitov (ORCID: https://orcid.org/0000-0002-7021-2012)
- Rachel Sarig (ORCID: https://orcid.org/0000-0002-4132-5114)
- Zachary Petrover
- David Kain (ORCID: https://orcid.org/0000-0002-8410-9390)
- Christian Kupatt (ORCID: https://orcid.org/0000-0002-3611-1218)
- Alessandra Moretti (ORCID: https://orcid.org/0000-0001-5782-7832)
- Eldad Tzahor (ORCID: https://orcid.org/0000-0002-5212-9426)
- Jacob Elkahal (ORCID: https://orcid.org/0000-0003-0157-7162)
- Kfir Baruch Umansky (ORCID: https://orcid.org/0000-0003-0541-3069)
- Achim Krüger (ORCID: https://orcid.org/0000-0002-1517-9256)
- Danielle M. Kimchi
- Elad Bassat (ORCID: https://orcid.org/0000-0001-5851-052X)
- Alexander Genzelinakh
- Avi Mayo (ORCID: https://orcid.org/0000-0002-4479-3423)
- Eviatar Weizman (ORCID: https://orcid.org/0000-0001-6549-891X)
- Avraham Shakked (ORCID: https://orcid.org/0000-0003-2978-7145)
- Daniel Häußler (ORCID: https://orcid.org/0000-0003-0658-3262)
- Lingling Zhang (ORCID: https://orcid.org/0000-0001-7423-3761)
- Uri Alon (ORCID: https://orcid.org/0000-0001-6903-9956)
- Andrea Baehr
- Hanna Bueno-Levy
Institutions
- Institute of Molecular Biotechnology (AT)
- European Bioinformatics Institute (GB)
- Howard Hughes Medical Institute (US)
- Research Institute of Molecular Pathology (AT)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- TUM Klinikum (DE)
- Yale University (US)
- German Centre for Cardiovascular Research (DE)
- Vienna Biocenter (AT)
- Weizmann Institute of Science (IL)
- Technical University of Munich (DE)
Publication Details
- Journal
- Cell Systems
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1016/j.cels.2025.101198
- Citations
- 17
- Primary Topic
- Cardiac Fibrosis and Remodeling
- Type
- article
- Field-Weighted Citation Impact
- 23.60
Funders
- Cancer Research UK
- Deutsche Forschungsgemeinschaft
- Israel Science Foundation
- FP7 Coordination of Research Activities
- H2020 European Research Council