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Cold and hot fibrosis define clinically distinct cardiac pathologies

ABSTRACT: Fibrosis is a pathology of excessive scarring and a major unmet medical need. Identifying key simplifying principles is needed to better understand fibrosis and may yield new therapeutic approaches. Fibrosis is driven by myofibroblasts that interact with macrophages. We developed a cell-circuit model that predicted two types of fibrosis - ‘hot fibrosis’ that includes both macrophages and myofibroblasts, and ‘cold fibrosis’ dominated by myofibroblasts alone. Here, we tested these concepts using an in-vivo pathological model for cardiac fibrosis resulting from myocardial infarction (MI). We show that MI progresses into cold fibrosis in both mice and pigs. We used the cell-circuit model to find a fragility of cold fibrosis - the autocrine loop which supports myofibroblast growth. We identified the growth factors in the autocrine loop and demonstrate that one of these factors- TIMP1- can stimulate cardiac myofibroblast proliferation in vitro. Inhibiting TIMP1 in-vivo reduced fibrosis in adult mice after MI. This study demonstrates the concept of cold fibrosis following acute MI and the feasibility of our circuit-to-target approach to better understand and treat fibrosis.

ORGANISM(S): Sus scrofa

PROVIDER: GSE247856 | GEO | 2025/02/18

REPOSITORIES: GEO

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Cold and hot fibrosis define clinically distinct cardiac pathologies

Project description:Fibrosis is a broad pathology of excessive scarring with substantial medical implications. The fibrotic scar is produced by myofibroblasts that interact with macrophages. Fibrosis is a complex process involving thousands of factors, therefore, to better understand fibrosis and develop new therapeutic approaches, it is necessary to simplify and clarify the underlying concepts. Recently, we described a mathematical model for a macrophage-myofibroblast cell circuit, predicting two types of fibrosis - hot fibrosis with abundant macrophages and myofibroblasts, and cold fibrosis dominated by myofibroblasts alone. To test these concepts and intervention strategies in a medically relevant system, we use a widely studied in-vivo injury model for fibrosis, myocardial infarction (MI). We show that cold fibrosis is the final outcome of MI in both mice and pigs and demonstrate that fibrosis can shift toward healing in regenerative settings. MI begind with an increase of myofibroblasts and macrophages, followed by macrophage decline leading to persistent cold fibrosis (only myofibroblasts). During this process, fibroblasts, unlike macrophages, acquire distinct fate changes. Using mathematical modeling we predict that targeting of the autocrine signal for myofibroblast division could block cold fibrosis. We identify TIMP1 as an autocrine cardiac myofibroblast growth factor in-vitro. Treatment of adult mice after MI with anti-TIMP1 antibodies reduces fibrosis in-vivo. This study shows the utility of the concepts of hot and cold fibrosis and the feasibility of our circuit-to-target approach to reduce fibrosis after acute cardiac injury by inhibiting the myofibroblast autocrine loop.

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