PW1+ cells give rise to cardiac adipocytes during development and myofibroblasts following injury.

BACKGROUND

Pw1, a maternally imprinted gene, is expressed in various stem cell populations, underscoring its crucial roles in tissue development, maintenance, and regeneration. While our recent work has revealed its regulatory function in cardiac fibrosis following ischemic injury, whether PW1+ cells exhibit stem cell properties in the heart remains unclear.

METHODS

We utilized genetic lineage tracing with Pw1pCreER/m+;R26-tdT and Pw1p2A-CreER/m+;R26-tdT mouse models. The adipogenic and fibrogenic potential of PW1+ cells was assessed in vitro using sorted tdTomato+ cells subjected to differentiation assays. In vivo fate mapping was performed during postnatal development and after myocardial infarction (MI) induced by permanent coronary artery ligation. Single-cell RNA sequencing data from adult mouse hearts were reanalyzed to characterize Pw1 expression across cardiac cell types.

RESULTS

PW1 was expressed in multiple cardiac cell types-such as mesenchymal cells, epicardial cells, and endothelial cells-during early postnatal development. Isolated PW1+ cells from infant hearts differentiated into adipocytes in vitro, and lineage tracing experiments confirmed their significant contribution to cardiac adipocyte formation throughout postnatal development. Single-cell transcriptomic analysis further revealed predominant Pw1 expression in adult cardiac fibroblasts. In vitro, adult PW1+ cells differentiated into myofibroblasts upon TGFb1 stimulation and showed upregulated expression of extracellular matrix genes and TGFb receptors. After MI, PW1+ cells preferentially expanded and contributed to the myofibroblast population within the infarcted region.

CONCLUSION

This study reveals that PW1+ cells serve as a progenitor population capable of generating cardiac adipocytes during postnatal development and contributing to myofibroblast formation after MI. These findings offer new insights into cardiac adipogenesis and fibrogenesis, providing a potential foundation for future therapies aimed at mitigating pathological adipose accumulation and fibrosis in the heart.