Leptin Receptor Fibroblasts Are Preferential Contributors to Cardiac Fibrosis

BACKGROUND: Cardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of preexisting cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. METHODS: Murine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction. Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq data sets and histological examination. RESULTS: In mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the LepR (leptin receptor). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin. After myocardial infarction, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. CONCLUSIONS: These findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease.

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Publication Details

Journal
Circulation Research
Published
2026-04-16
DOI
https://doi.org/10.1161/circresaha.125.327701
Primary Topic
Cardiovascular Function and Risk Factors
Type
article
Field-Weighted Citation Impact
0.00
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article

Leptin Receptor Fibroblasts Are Preferential Contributors to Cardiac Fibrosis

Ariane Fischer, Lunfeng Zhang, Sofia Peruzzo, Serena Zacchigna et al.
Circulation Research
Cardiovascular Function and Risk Factors
article

Leptin Receptor Fibroblasts Are Preferential Contributors to Cardiac Fibrosis

Ariane Fischer, Lunfeng Zhang, Sofia Peruzzo, Serena Zacchigna, Stefanie Dimmeler, Francesca Andriani, Rossana Bussani, Simone Serio, Ralf H. Adams, Veronica Larcher, Sylvia Μ. Evans, Mattia Chiesa, Lukas Tombor, Nuno Guimarães‐Camboa, Paola Cattaneo, Debanjan Mukherjee, Omar Almolla, Chiara Wernet
article en

Abstract

BACKGROUND: Cardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of preexisting cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. METHODS: Murine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction. Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq data sets and histological examination. RESULTS: In mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the LepR (leptin receptor). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin. After myocardial infarction, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. CONCLUSIONS: These findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease.

Circulation Research
Goethe University Frankfurt (DE), University of Trieste (IT), University of Milan (IT), University of California San Diego (US), Centro Cardiologico Monzino (IT), Institute of Genetic and Biomedical Research (IT), German Centre for Cardiovascular Research (DE), Max Planck Institute for Molecular Biomedicine (DE), Cardio-Pulmonary Institute (DE), National Research Council (IT), IRCCS Humanitas Research Hospital (IT), University of Montana (US), International Centre for Genetic Engineering and Biotechnology (IT), Politecnico di Milano (IT)
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