Fig. 2.

Developmental signaling factors for adult heart regeneration. Manipulation of thyroid hormone signaling, substrate availability and utilization, and oxygen levels (hypoxia) influence cardiomyocyte proliferation and heart regeneration by mainly targeting cellular metabolism. Attenuation of oxidative metabolism leads to a reduction in reactive oxygen species and subsequent oxidative DNA damage, one of the main mechanisms in postnatal cell cycle arrest. Reactivation of the active form of YAP (Hippo pathway) reprograms chromatin acessibility to enhance cell cycle regulators, while blunting Meis1 or alteration in miRNAs levels can directly upregulate cell cycle genes or downregulate cell cycle inhibitors and cardiomyocyte proliferation. Reintroduction of Lamin B2 enhances nuclear division decreasing ploidy levels, a known contributor in postnatal cell cycle arrest.