Identification of a multipotent Twist2-expressing cell population in the adult heart

Twist transcription factors function as ancestral regulators of mesodermal cell fates in organisms ranging from Drosophila to mammals. Through lineage tracing of Twist2 (Tw2)-expressing cells with tamoxifen-inducible Tw2-CreERT2 and tdTomato (tdTO) reporter mice, we discovered a unique cell population that progressively contributes to cardiomyocytes (CMs), endothelial cells, and fibroblasts in the adult heart. Clonal analysis confirmed the ability of Tw2-derived tdTO⁺ (Tw2-tdTO⁺) cells to form CMs in vitro. Within the adult heart, Tw2-tdTO⁺ CMs accounted for ∼13% of total CMs, the majority of which resulted from fusion of Tw2-tdTO⁺ cells with existing CMs. Tw2-tdTO⁺ cells also contribute to cardiac remodeling after injury. We conclude that Tw2-tdTO⁺ cells participate in lifelong maintenance of cardiac function, at least in part through de novo formation of CMs and fusion with preexisting CMs, as well as in the genesis of other cellular components of the adult heart.