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

Summary

Using fibroblast-specific TGF-β receptor (TbR2) deletion, the authors show that loss of TGF-β signaling increases early post-MI rupture risk and replaces 30–40% of mature scar with adipocytes, via fibroblast-to-adipocyte conversion. Lineage tracing and in vitro assays demonstrate that TbR2 inhibition primes cardiac fibroblasts for adipogenesis, and human infarct fibroblasts exhibit adipocyte gene expression, indicating translational relevance.

Key Findings

• Fibroblast-specific TbR2 deletion increased early post-infarction cardiac rupture and induced a matrix-degrading fibroblast phenotype.
• TbR2 loss replaced 30–40% of mature scar with adipocytes in both reperfused and nonreperfused MI models via fibroblast-to-adipocyte conversion.
• In vitro TbR2 inhibition upregulated adipogenesis genes in cardiac fibroblasts; human infarct fibroblasts exhibited adipocyte gene expression by scRNA-seq.

Clinical Implications

Interventions that preserve or modulate TGF-β signaling in cardiac fibroblasts may prevent fatty scar formation, potentially reducing arrhythmogenesis and adverse remodeling after MI. Caution is warranted for systemic TGF-β pathway inhibition in post-MI settings.

Limitations

• Preclinical models; clinical causality and safety of pathway modulation remain untested.
• Quantitative human tissue validation is limited to transcriptional evidence rather than functional perturbation.

Future Directions

Test selective, timed TGF-β pathway modulation post-MI to prevent lipomatous metaplasia and arrhythmia in large animals, and develop imaging biomarkers to detect adipogenic scar in patients.