Abstract Or102: A Cellular Mechanism Mediating Lipomatous Metaplasia In the Infarcted Heart.

Objectives: In patients surviving myocardial infarction (MI), adipose tissue infiltration within the scar is a common pathologic finding and may contribute to dysfunction and arrhythmogenesis. However, the cellular mechanisms for lipomatous metaplasia after MI remain enigmatic. We reveal a novel molecular mechanism that mediates fibroblast to adipocyte conversion and causes fatty infiltration in the infarcted heart. Methods: Mice with inducible fibroblast-specific disruption of Transforming Growth Factor (TGF)-β (through deletion of TGF-β receptor 2 (TbR2), the only type 2 receptor that mediates effects of the 3 TGF-β isoforms) or Smad-dependent signaling and corresponding controls were generated and underwent MI. Histological studies were performed to study effects on cardiac repair. Lineage tracing experiments were used to document fibroblast to adipocyte conversion. In vitro, the effects of TGF-β signaling blockade on the transcriptome of mouse cardiac fibroblasts were examined. Results: Fibroblast-specific TbR2 knockout (FTbR2KO) increased early post-MI cardiac rupture and resulted in replacement of 34.1+4.5% of the mature scar with adipocytes (vs 0% in Cre+ control infarcts, p<0.0001) (Fig. 1). Lineage tracing showed that adipocytes infiltrating the scars of FTbR2KO mice were derived from fibroblasts (Fig. 1). Histological analyses of the hearts from mice with inducible fibroblast-specific loss of Smad4 (the common Smad responsible for all Smad signaling) demonstrated absence of lipomatous metaplasia post MI, suggesting that loss of Smad-independent TGF-β signaling triggers fibroblast to adipocyte conversion. In vitro, TbR2 inhibition induced expression of the adipogenesis-associated genes, such as Lpl , Klf4 , Tcf7l2 , Mapk14 , Ddit3 , and Bmp4 in primary cardiac fibroblasts. Analysis of scRNA-seq data from human MI showed that fibroblasts in late-stage infarcts have increased expression of the adipocyte genes Plin1, Pparg, Adipoq and Zbtb16 . Pseudotime trajectory analysis suggested that expression of adipocyte genes in infarct fibroblasts exhibits a time-dependent increase, consistent with progressive fibroblast to adipocyte conversion. Conclusions: TGF-β signaling maintains fibroblast cell specification post MI. Fibroblast to adipocyte conversion induced by disrupted Smad-independent TGF-β signaling underlies scar-associated lipomatous metaplasia and may contribute to the pathogenesis of heart failure and arrhythmogenesis in ischemic cardiomyopathy.