Fibroblast-Specific Loss of TGF-β Signaling Mediates Lipomatous Metaplasia in the Infarcted Heart

BACKGROUND: In patients surviving myocardial infarction, adipose tissue infiltration within the scar is a common pathological finding and has been suggested to contribute to dysfunction and arrhythmogenesis. However, the cellular mechanisms for lipomatous metaplasia after infarction remain enigmatic. Our study reveals a novel molecular mechanism that mediates fibroblast-to-adipocyte conversion and causes fatty infiltration in the infarcted heart. METHODS: Mice with fibroblast-specific disruption of TGF-β (transforming growth factor-β) or Smad-dependent signaling and corresponding controls were generated and underwent reperfusion and nonreperfusion myocardial infarction protocols. Echocardiography, histological studies, and transcriptomic analysis were used to study effects on cardiac repair and remodeling. Lineage tracing experiments were used to document fibroblast-to-adipocyte conversion. In vitro, the effects of genetic disruption or pharmacological blockade of TGF-β signaling on mouse cardiac fibroblasts were examined. Single-cell RNA sequencing data from human patients with myocardial infarction were analyzed to assess fibroblast-to-adipocyte conversion. RESULTS: Fibroblast-specific abrogation of TGF-β signaling through deletion of TbR2 (type 2 TGF-β receptor) increased the incidence of early postinfarction cardiac rupture, promoting a matrix-degrading fibroblast phenotype. Moreover, fibroblast-specific TbR2 loss resulted in replacement of 30% to 40% of the mature scar with adipocytes in both reperfused and nonreperfused infarcts. Lineage tracing demonstrated that fibroblast-specific TbR2 loss promotes fibroblast-to-adipocyte conversion through effects that involve Smad-independent cascades. In vitro, TbR2 inhibition induced expression of adipogenesis-associated genes in primary cardiac fibroblasts. Genetic TbR2 loss promoted conversion of infarct fibroblasts to adipocytes upon stimulation with adipogenic medium. A subpopulation of fibroblasts in human fibrotic infarcted hearts acquired expression of adipocyte genes. CONCLUSIONS: TGF-β signaling plays a central role in maintaining fibroblast cell specification after cardiac injury. Fibroblast-to-adipocyte conversion induced by disrupted TGF-β signaling may underlie scar-associated lipomatous metaplasia and may play an important role in the pathogenesis of heart failure and arrhythmogenesis in patients with ischemic cardiomyopathy.