image: The ACM mouse model is established by inactivating desmosomal gene Dsp in cardiomyocytes. Then the mutant hearts exhibit obvious and noticeable adipocyte formation in the ventricle walls. Genetic lineage tracing identifies that the SOX9+, PDGFRa+ and PDGFRb+ mesenchymal cells, but not cardiomyocytes or smooth muscle cells, are the cellular origins of cardiac adipocytes. In addition, Bmp4 is highly expressed in the hearts of ACM model and may be involved in cardiac mesenchymal-to-adipose transition. view more
Credit: ©Science China Press
This study is led by Dr. Hui Zhang (School of Life Science and Technology, ShanghaiTech University), Dr. Ping Zhu (Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences) and Dr. Juan Tang (Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Science and Technology, Tongji University). ACM is a hereditary cardiomyopathy characterized by fibrofatty replacement of the ventricular myocardium, a high risk of life-threatening ventricular arrhythmias, sudden cardiac death, and progressive heart failure (Basso et al., 2009). However, the cellular origin of cardiac adipocytes in ACM remains largely unknown.
The research team established an ACM mouse model using the inducible Myh6-MerCreMer (Myh6-MCM) to delete the floxed Dsp gene (Dspfl) specifically in cardiomyocytes (Sohal et al., 2001; Vasioukhin et al., 2001). Sirius red and Oil Red O staining showed obvious fibrosis and adipocyte accumulation in the ACM mouse hearts. Echocardiographic analyses also demonstrated deteriorated heart function of the ACM mice. Then, researchers studied the adipogenic potential of cardiomyocytes and mesenchymal cells in the model. First, they crossed the Myh6-MCM;Dspfl/fl mice with a reporter line Rosa26-loxp-stop-loxp-tdTomato (R26-tdT) (Madisen et al., 2010) to investigate the contribution of cardiomyocytes to adipocytes in the ACM mouse hearts. It was found that cardiomyocytes did not give rise to cardiac adipocytes in the model. Next, researchers examined the contribution of mesenchymal cells to cardiac adipocytes in the model by employing various mouse tools, which can target different mesenchymal subpopulations (e.g., fibroblasts, vascular pericytes and smooth muscle cells) in mouse hearts. It was found that the SOX9+, PDGFRa+ and PDGFRb+ mesenchymal cell populations, but not smooth muscle cells, gave rise to cardiac adipocytes in the ACM model. Furthermore, the researchers found that Bmp4 was highly enriched in the ventricles of the ACM mouse hearts and might participate in promoting cardiac mesenchymal-to-adipose transition in the model. This study clarifies the cellular origin of cardiac adipocytes in an ACM model and provides in-depth insights into understanding the pathogenesis and adipogenesis of ACM.
See the article:
Genetic lineage tracing identifies cardiac mesenchymal-to-adipose transition in an arrhythmogenic cardiomyopathy model
https://doi.org/10.1007/s11427-022-2176-6
Journal
Science China Life Sciences