Table 4.

Signaling pathways that influence cardiomyocyte cell cycle entry.

Pathway	Studied Species	Highlights	References
PI3K-AKT	Isolated rat cardiomyocytes	Activating the PI3K-AKT signaling pathway showed a successful induction of mitosis and cytokinesis	[74]
Hippo signaling pathway	Neonatal and adult mice cardiomyocytes. Transgenic mice	Active version could program adult mice cardiomyocytes to a fetal heart program with high proliferation capacity and increased chromatin accessibility. Cardiac-specific deletion of YAP in mice was associated with impaired cardiac functions with ventricular wall fibrosis Overexpressing a constitutively active YAP showed enhanced proliferative capacity and increased PHH3 expression after LAD artery ligation in P7 day old neonatal mice	[81,82,83]
Notch signaling pathway	Zebrafish	Suppression of Notch signaling in zebrafish impaired their capacity to regenerate their heart after ventricular resection	[86]
Wnt/β-catenin	sFRP2 and GSK3 β knockout mice	Knockout of sFRP2 protein showed reduced fibrosis and improved cardiac functions after MI GSK3β knockout activated Wnt/β-catenin, which increased cyclin D and allowed the cardiomyocytes to proceed into the S phase.	[89,90,91]
Jak/Stat	Zebrafish Adult mice cardiomyocytes	Stat3 facilitates cell cycle re-entry Stat3 inhibition was associated with a limited ability of cardiomyocytes to proliferate and increased scarring in response to injury	[92,93]
Hedgehog (Hh)	Zebrafish Newts	Hh signaling stimulated the expression of cyclin D2 and cyclin E1 and inhibited P27 through Gli1–Mycn network interaction	[102]
Autonomic innervation	Zebrafish Mice Human pediatric patients with F4	Chemical sympathectomy inhibited cardiac regeneration after apical resection β-adrenergic receptor stimulation in patients with tetralogy of Fallot (F4) was linked to cardiomyocyte cell cycle arrest Inhibitions of cholinergic nerve functions diminished cardiomyocyte proliferation Cholinergic stimulation extended the postnatal cardiomyocyte regeneration window	[103,104,105]