冷纤维化和热纤维化定义了临床上不同的心脏病理。

Cell systems Pub Date : 2025-03-19 Epub Date: 2025-02-18 DOI:10.1016/j.cels.2025.101198
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
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引用次数: 0

摘要

纤维化仍然是一个主要的未满足的医疗需求。为了更好地理解纤维化并产生新的治疗方法,需要简化原理。纤维化是由与巨噬细胞相互作用的肌成纤维细胞驱动的。一个数学细胞回路模型预测了两种类型的纤维化:由巨噬细胞和肌成纤维细胞驱动的热纤维化和仅由肌成纤维细胞驱动的冷纤维化。在心肌梗死(MI)和心力衰竭(HF)引起的心脏纤维化中测试这些概念,我们发现急性心肌梗死导致冷纤维化,而慢性损伤(HF)导致热纤维化。心肌梗死驱动的冷纤维化在猪和人类中都是保守的。我们通过计算确定了冷纤维化的一个易感性:肌成纤维细胞自分泌生长因子环。通过中和抗体靶向TIMP1抑制该环,可减少小鼠心肌梗死后肌成纤维细胞增殖和纤维化。我们的研究证明了热纤维化和冷纤维化概念的实用性,以及回路到靶标方法的可行性,以确定减少纤维化的治疗策略。本文的透明同行评议过程记录包含在补充信息中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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