Table 1.

– Strategies reactivating developmental signaling in adult hearts.

developmental signaling factors	Neonatal heart	Adult heart	Main altered pathways
Environmental factors
Oxygen tension	Low Oxygen saturation	Highly oxygenated	↓ OxPHOS ↓ ROS / DNA damage
Thyroid hormone	Decreased	Increased	↓ Ploidy ↓ OxPHOS ↑ Cell cycle regulators ↑ G2/M checkpoints ↑ E2F targets ↓ Muscle contraction
Mitochondria substrate utilization	Glucose	Fatty acids	↑ Pyruvate oxidation ↓ ROS / DNA damage ↑ Cell cycle regulators (Ccnd1, Cdc6, and E2f1) ↓ CDK inhibitors (Cdk1a, Cdk1c)
Cellular and molecular factors
Meis1	Downregulated	Upregulated	↓ CDK inhibitors (p15, p16 and p21) ↑ Cell cycle regulators (MCM3, Chek1 and Ccnd2)
YAP (YAP5SA)	Upregulated	Downregulated	Chromatin remodeling to a fetal-like state ↑ Cell cycle regulators (Ccnd1, Ccna2, Ccnb2, and Ccnb1) ↓ Sarcomeric proteins (MYH6 and TNNT1) ↑ Mononucleate and diploid CMs ↑ IGF-1 and Akt signaling
Cell cycle regulators (CDK1, CDK4, cyclins B1 and D1)	Upregulated	Downregulated	↑ G2/M phase progression ↓ DNA damage
Pkm2	Upregulated	Downregulated	↑ G6pd and PPP pathway ↓ ROS / DNA damage ↑ Cyclin D1 and c-Myc
Lamin B2	Upregulated	Downregulated	↓ Ploidy ↑ Karyokinesis
miR-15	Downregulated	Upregulated	↓ Sarcomere organization ↑ Cell cycle genes
miR-294	Upregulated	Downregulated	↑ Glycolysis and OxPHOS ↑ Cell cycle regulators (Cyclins B1, D1, E1 and A2, CDK1, E2F1, and E2F3) ↓ Negative cell cycle regulators (Wee1)
miR17–92 cluster	Upregulated	Downregulated	↓ PTEN

OxPhos – Oxidative phosphorylation; ROS – Reactive oxygen species; CMs – Cardiomyocytes; PPP - Pentose phosphate pathway.