Metabolic reprograming-driven programmed embryonic cardiomyocyte senescence shapes cardiac chambers

The growing and yet beating embryonic heart requires nutriments and oxygenation. In the absence of the coronary system to feed the organ up to mid-gestation, formation of the heart relies on transient trabeculae that extend from the myocardial wall into the chamber and increase exchange surface. How trabeculae are formed has been recently uncovered. How they coalesce during ventricular wall thickening and compaction is a long-lasting and still unresolved question, while their persistence after birth provides the young patient with a high risk of heart failure at adulthood. Here, we combine single cell-omics, pharmacological and genetic invalidations of proteins in mice, High Resolution Episcopic Microscopy and 3D heart imaging to report that a TGF- and a metabolism-driven program of embryonic senescence occurs at mid-gestation in both mouse and human trabeculae cardiomyocytes. The senescent myocytes with a unique transcriptomic signature induce reprograming of neighbor myocytes. Dedifferentiated myocytes undergo YAP-mediated EMT, proliferate and contribute to the thickening of the ventricular wall. Macrophages terminate the whole process by scavenging senescent myocytes further leading to a regression of trabeculae and initiation of ventricular compaction. Deletion of cdkn1a(p21), inhibition of TGF signaling, perturbation of metabolism or deletion of embryonic macrophages leads to hyper-trabeculation, and defects in compaction. Exacerbation of cardiomyocyte senescence by a cyclin-dependent kinases 4/6 inhibitor unbalances the biological process and leads to non-compaction and dilated cardiomyopathy. We show that a myocardial specific and finely-tuned program of embryonic cell senescence, conserved during evolution initiates cardiac compaction allowing for a proper patterning of cardiac chambers