Cold and hot fibrosis define clinically distinct cardiac pathologies

Shoval Miyara; Miri Adler; Kfir B. Umansky; Daniel Häußler; Elad Bassat; Yalin Divinsky; Jacob Elkahal; David Kain; Daria Lendengolts; Ricardo O. Ramirez Flores; Hanna Bueno-Levy; Ofra Golani; Tali Shalit; Michael Gershovits; Eviatar Weizman; Alexander Genzelinakh; Danielle M. Kimchi; Avraham Shakked; Lingling Zhang; Jingkui Wang; Andrea Baehr; Zachary Petrover; Rachel Sarig; Tatjana Dorn; Alessandra Moretti; Julio Saez-Rodriguez; Christian Kupatt; Elly M. Tanaka; Ruslan Medzhitov; Achim Krüger; Avi Mayo; Uri Alon; Eldad Tzahor

doi:10.1016/j.cels.2025.101198

Cold and hot fibrosis define clinically distinct cardiac pathologies

Shoval Miyara
, Miri Adler
, Kfir B. Umansky
, Daniel Häußler
, Elad Bassat
, Yalin Divinsky
, Jacob Elkahal
, David Kain
, Daria Lendengolts
, Ricardo O. Ramirez Flores
, Hanna Bueno-Levy
, Ofra Golani
, Tali Shalit
, Michael Gershovits
, Eviatar Weizman
, Alexander Genzelinakh
, Danielle M. Kimchi
, Avraham Shakked
, Lingling Zhang
, Jingkui Wang

Andrea Baehr, Zachary Petrover, Rachel Sarig, Tatjana Dorn, Alessandra Moretti, Julio Saez-Rodriguez, Christian Kupatt, Elly M. Tanaka, Ruslan Medzhitov, Achim Krüger, Avi Mayo, Uri Alon^*, Eldad Tzahor^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

567 Downloads (Pure)

Abstract

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.

Original language	English
Article number	101198
Number of pages	32
Journal	Cell Systems
Volume	16
Issue number	3
DOIs	https://doi.org/10.1016/j.cels.2025.101198
Publication status	Published - 19 Mar 2025

Funding

We thank Marina Cohen from the Histology Unit, Department of Veterinary Resources, Weizmann Institute of Science for histological processing and staining. We also thank Dr. Hadas Keren-Shaul and Danna Robbins (The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science) for pig bulk-mRNA sequencing library preparation and sequencing. We would like to acknowledge histology and next-generation sequencing facilities at the Vienna Biocenter Core Facilities (VBCF) for all aspects of Visium handling, sectioning, and sequencing. We thank Prof. Steffen Jung, Dr. Jung-Seok Kim, and Dr. Sebastien Trzebanski from the Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel for insightful comments and technical assistance in flow cytometry experiments. This study has been supported by grants to E.T. from the European Research Council (ERC AdG grant no. 788194, CardHeal), REANIMA European Union's Framework Programme for Research and Innovation \u201CHorizon2020.\u201D E.T. and R.S. were supported by the Israel Science Foundation (ISF, no. 2214/22). This study was further supported by a Cancer Research UK grant (C19767/A27145) and by the European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement No. 856487) to U.A. M.A. was supported by the EMBO Long-Term Fellowship (ALTF 304-2019), the Zuckerman STEM Leadership program, and the Israel National Postdoctoral Award Program for Advancing Women in Science. C.K. was funded by the ERC Advanced Grant Cor-Edit-P (grant no. 101021043). E.M.T. was funded by REANIMA European Union's Framework Programme for Research and Innovation \u201CHorizon2020\u201D and FWF P36045 \u201CRegenerative strategies for cardiac repair.\u201D E.B was funded by the EMBO ALTF447-2020 and the Marie Curie Post-doctoral individual fellowship \u201CAxomatrx.\u201D A.K. and D.H. were funded by the Deutsche Forschungsgemeinschaft, Bonn, Germany (KR2047/8-2, KR2047/14-1, and KR2047/15-1). E.T. is a Founder of a biomedical startup related to Agrin therapy for heart disease and has related patents. J.S.-R. reports funding from GSK, Pfizer, and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Pfizer, Grunenthall, Moderna, and Owkin. We thank Marina Cohen from the Histology Unit, Department of Veterinary Resources, Weizmann Institute of Science for histological processing and staining. We also thank Dr. Hadas Keren-Shaul and Danna Robbins (The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science) for pig bulk-mRNA sequencing library preparation and sequencing. We would like to acknowledge histology and next-generation sequencing facilities at the Vienna Biocenter Core Facilities (VBCF) for all aspects of Visium handling, sectioning, and sequencing. We thank Prof. Steffen Jung, Dr. Jung-Seok Kim, and Dr. Sebastien Trzebanski from the Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel for insightful comments and technical assistance in flow cytometry experiments. This study has been supported by grants to E.T. from the European Research Council (ERC AdG grant no. 788194 , CardHeal), REANIMA European Union\u2019s Framework Programme for Research and Innovation \u201CHorizon2020,\u201D and the Israel Science Foundation (ISF, no. 713/18 , 2214/22 ) and by a Cancer Research UK ( C19767/A27145 ) to U.A. M.A. was supported by the EMBO Long-Term Fellowship ( ALTF 304-2019 ), the Zuckerman STEM Leadership program , and the Israel National Postdoctoral Award Program for Advancing Women in Science . C.K. was funded by the ERC Advanced Grant Cor-Edit-P (grant no. 101021043 ). E.M.T. was funded by REANIMA European Union's Framework Programme for Research and Innovation \u201CHorizon2020\u201D and FWF P36045 \u201CRegenerative strategies for cardiac repair.\u201D E.B was funded by the EMBO LTF and the Marie Curie Post-doctoral program. A.K. and D.H. were funded by the Deutsche Forschungsgemeinschaft, Bonn, Germany ( KR2047/8-2 , KR2047/14-1 , and KR2047/15-1 ).

All Science Journal Classification (ASJC) codes

Pathology and Forensic Medicine
Histology
Cell Biology

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10.1016/j.cels.2025.101198Licence: CC BY

ua_CellSys_ColdandHotFibrosisDefine_PV2025Final published version, 8.46 MBLicence: CC BY

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Miyara, S., Adler, M., Umansky, K. B., Häußler, D., Bassat, E., Divinsky, Y., Elkahal, J., Kain, D., Lendengolts, D., Ramirez Flores, R. O., Bueno-Levy, H., Golani, O., Shalit, T., Gershovits, M., Weizman, E., Genzelinakh, A., Kimchi, D. M., Shakked, A., Zhang, L., ... Tzahor, E. (2025). Cold and hot fibrosis define clinically distinct cardiac pathologies. Cell Systems, 16(3), Article 101198. https://doi.org/10.1016/j.cels.2025.101198

@article{be6e078833f446fe9ca6c3e86175e626,

title = "Cold and hot fibrosis define clinically distinct cardiac pathologies",

abstract = "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.",

author = "Shoval Miyara and Miri Adler and Umansky, \{Kfir B.\} and Daniel H{\"a}u{\ss}ler and Elad Bassat and Yalin Divinsky and Jacob Elkahal and David Kain and Daria Lendengolts and \{Ramirez Flores\}, \{Ricardo O.\} and Hanna Bueno-Levy and Ofra Golani and Tali Shalit and Michael Gershovits and Eviatar Weizman and Alexander Genzelinakh and Kimchi, \{Danielle M.\} and Avraham Shakked and Lingling Zhang and Jingkui Wang and Andrea Baehr and Zachary Petrover and Rachel Sarig and Tatjana Dorn and Alessandra Moretti and Julio Saez-Rodriguez and Christian Kupatt and Tanaka, \{Elly M.\} and Ruslan Medzhitov and Achim Kr{\"u}ger and Avi Mayo and Uri Alon and Eldad Tzahor",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s)",

year = "2025",

month = mar,

day = "19",

doi = "10.1016/j.cels.2025.101198",

language = "English",

volume = "16",

journal = "Cell Systems",

issn = "2405-4712",

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Miyara, S, Adler, M, Umansky, KB, Häußler, D, Bassat, E, Divinsky, Y , Elkahal, J, Kain, D, Lendengolts, D, Ramirez Flores, RO, Bueno-Levy, H , Golani, O , Shalit, T, Gershovits, M, Weizman, E, Genzelinakh, A, Kimchi, DM, Shakked, A, Zhang, L, Wang, J, Baehr, A, Petrover, Z , Sarig, R, Dorn, T, Moretti, A, Saez-Rodriguez, J, Kupatt, C, Tanaka, EM, Medzhitov, R, Krüger, A, Mayo, A , Alon, U & Tzahor, E 2025, 'Cold and hot fibrosis define clinically distinct cardiac pathologies', Cell Systems, vol. 16, no. 3, 101198. https://doi.org/10.1016/j.cels.2025.101198

TY - JOUR

T1 - Cold and hot fibrosis define clinically distinct cardiac pathologies

AU - Miyara, Shoval

AU - Adler, Miri

AU - Umansky, Kfir B.

AU - Häußler, Daniel

AU - Bassat, Elad

AU - Divinsky, Yalin

AU - Elkahal, Jacob

AU - Kain, David

AU - Lendengolts, Daria

AU - Ramirez Flores, Ricardo O.

AU - Bueno-Levy, Hanna

AU - Golani, Ofra

AU - Shalit, Tali

AU - Gershovits, Michael

AU - Weizman, Eviatar

AU - Genzelinakh, Alexander

AU - Kimchi, Danielle M.

AU - Shakked, Avraham

AU - Zhang, Lingling

AU - Wang, Jingkui

AU - Baehr, Andrea

AU - Petrover, Zachary

AU - Sarig, Rachel

AU - Dorn, Tatjana

AU - Moretti, Alessandra

AU - Saez-Rodriguez, Julio

AU - Kupatt, Christian

AU - Tanaka, Elly M.

AU - Medzhitov, Ruslan

AU - Krüger, Achim

AU - Mayo, Avi

AU - Alon, Uri

AU - Tzahor, Eldad

PY - 2025/3/19

Y1 - 2025/3/19

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105000021577

U2 - 10.1016/j.cels.2025.101198

DO - 10.1016/j.cels.2025.101198

M3 - Article

C2 - 39970910

AN - SCOPUS:105000021577

SN - 2405-4712

VL - 16

JO - Cell Systems

JF - Cell Systems

IS - 3

M1 - 101198

ER -

Cold and hot fibrosis define clinically distinct cardiac pathologies

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