Table 2.

Major signaling pathways regulating heart regeneration

Mammalian pathways	Molecules	Experiments	Functions in CM Proliferation	References
Cdk/cyclin complex	cyclin D2	OE in adult mice	Increases DNA synthesis of CMs	Pasumarthi et al. 2005
	cyclin A2	OE in mice	Enhances CM proliferation and left ventricular systolic function	Chaudhry et al. 2004
	cyclin B1:CDC2	OE in rat CMs	Re-initiates cell division of adult rat CMs	Bicknell et al. 2004
	cyclin G1	OE in neonatal mice	Increases CM DNA synthesis but inhibits cytokinesis	Liu et al. 2010
	CDK1, CCNB, CDK4, CCND	OE in CMs	Induces mouse, rat, and human CM proliferation. Improves cardiac function after MI in mice	Mohamed et al. 2018
CDK inhibitors	p21, p27, p57	Combined knockdown	Promotes adult CM proliferation via increasing expression of cyclins A and E	Di Stefano et al. 2011; Tane et al. 2014
Upstream regulators	E2F1, E2F2	OE in adult mice	Increases DNA synthesis; increases CM apoptosis caused by OE of E2F1	Agah et al. 1997; Ebelt et al. 2008
Hippo	MST, LATS	KO	Induces CMs to re-enter the cell cycle	Heallen et al. 2013
	Salv	Knockdown or KO	Improves systolic cardiac function after MI in mice	Leach et al. 2017; Heallen et al. 2011
	YAP	Activation of YAP1 in mouse	Extends regenerative window in neonatal mouse heart and improves cardiac function after injury	Lin et al. 2014; Xin et al. 2013
		Constitutive activation	Makes adult CMs re-enter cell cycle by switching chromatin to a fetal-like and proliferative state	Monroe et al. 2019
		Administration of Agrin after MI	Enhances CMS proliferation in mice by interfering with YAP-DGC/DAG1 interaction	Bassat et al. 2017; Morikawa et al. 2017
Neuregulin	Nrg1/ErbB4	Nrg1 injection; ErbB4 OE or CKO	Nrg1 injection and ErbB4 OE promote CM proliferation after MI; CKO of ErbB4 in CMs reduces CM proliferation	Bersell et al. 2009; Polizzotti et al. 2015
	ErbB2	CKO in CMs	Reduces CM proliferation in embryonic or neonatal mouse	D'Uva et al. 2015
		Activation	Improves cardiac function post-MI
Notch	Notch1/Jagged1	Virus delivery	Induces neonatal mouse CM proliferation	Felician et al. 2014
Wnt	Wnt	Chemical inhibition	Promotes CM proliferation in infarcted border zone	Yang et al. 2017; Xie et al. 2020
MAPK	MKK3/6	OE in mice	Causes premature heart failure	Liao et al. 2001
	p38	Activation	Suppresses neonatal CM proliferation	Engel et al. 2005
		Attenuation of p38 activity	Causes cardiac hypertrophy and increases mitosis of CMs	Braz et al. 2003; Engel et al. 2005
	Dusp6	Disruption in neonatal heart	Increases CM proliferation	Maillet et al. 2008
TGFβ	Fstl1	Epicardial patch/ myocardial injection	Promotes CM proliferation and improves cardiac function in mouse and pig heart	Wei et al. 2015
Epigenetic regulators	miR-15 family	Knockdown in neonatal mice	Increases number of mitotic CMs	Porrello et al., 2011b
		Inhibition in adult mice	Reduces infarcted area after ischemia-reperfusion	Hullinger et al. 2012
	miR199a	AAV9-mediated OE	Promotes neonatal and adult rat CM proliferation; promotes repair after MI in mice	Eulalio et al. 2012
		OE in pigs	Improves cardiac repair after MI, but most treated pigs died suddenly due to arrhythmia	Gabisonia et al. 2019
	miR302-367	OE in adult mouse	Promotes CM proliferation by regulating MST and LATS	Tian et al. 2015
	CPR	CKO in mouse CMs	Increases CM proliferation and improves cardiac function	Ponnusamy et al. 2019
	cirNfix	Knockdown	Promotes CM proliferation	Huang et al. 2019
	Baf60c	Knockdown	Suppresses CM proliferation in neonatal mouse heart	Nakamura et al. 2016
Transcription factors	Meis1	CKO in mouse CMs	Drives mature CMs to re-enter cell cycle	Mahmoud et al. 2013
		OE	Inhibits heart regeneration in neonatal mice
	Gata4	Conditional KO	Leads to loss of regenerative ability in neonatal mice	Yu et al. 2016
	Tbx20	OE	Results in CM proliferation and improves cardiac function	Xiang et al. 2016
	REST	CKO in CMs	Inhibits CM proliferation in embryonic or adult mouse	Zhang et al. 2017
Zebrafish pathways	Molecules	Experiments	Functions in CM proliferation	References
Neuregulin	Nrg1	OE	Increases CM proliferation	Gemberling et al. 2015
	ErbB2	Inhibition	Reduces CM proliferation	Gemberling et al. 2015
	Vitamin D	Administration	Promotes CM proliferation dependent on Nrg1/ErbB2	Han et al. 2019
Notch	Mastermind-like	Conditional inhibition in ECs	Decreases CM proliferation	Zhao et al. 2019; Zhao et al. 2014
Wnt	Wnt	Chemical inhibition	Increases CM proliferation	Xie et al. 2020; Zhao et al. 2019
FGF	Fgfr1	OE of dn-Fgfr1	Blocks epicardial EMT, disrupting coronary neovascularization and arresting regeneration	Lepilina et al., 2006
PDGF	PDGF	Chemical inhibition	Reduces CM DNA synthesis and inhibits heart regeneration	Lien et al. 2006
MAPK	MKK6	OE	Impairs cardiogenesis and heart regeneration	Jopling et al. 2012
	p38α	Inactivation	Prerequisite to re-enter cell cycle	Jopling et al. 2012
	Dusp6	OE	Impairs heart regeneration	Han et al. 2014
		Deletion	Increases CM proliferation and decreases cardiac fibrosis	Missinato et al. 2018
	MEK1/2	Chemical inhibition	Down-regulates pERK and decreases CM proliferation	Liu and Zhong, 2017
		OE of dn-MEK1	Prevents angiogenesis and cardiac regeneration
TGFβ	TGFβ type I receptors	Chemical inhibition	Impairs heart regeneration by attenuating CM proliferation and enhancing scar formation	Chablais and Jazwinska, 2012; Choi et al. 2013
	Myostatin, inhbaa	Myostatin OE; inhbaa KO	Results in decreased CM proliferation	Dogra et al. 2017
		Myostatin KO; inhbaa OE	Causes hyperplasia and hypertrabeculation with late stage pericardial edema
VEGF	vegfa	OE in adult CMs	Leads to CM hyperplasia in absence of injury; impairs cardiac repair after injury	Karra et al. 2018
Jak/Stat3	Stat3	OE dn-Stat3 in CMs	Blocks regeneration in part by regulating Rln3a	Fang et al. 2013
Epigenetic	Brg1	Dn-Brg1 OE	Regulates CM proliferation by interacting with Dnmt3ab to increase methylation of cdkn1c promoter	Xiao et al. 2016
	H3K27me3	Conditional OE of H3.3K27M	Decreases K27me3 level and inhibits cardiac regeneration	Ben-Yair et al. 2019
	miR-101a	Depletion	Promotes CM proliferation at 3 dpa, but sustained inhibition of its expression increases fibrosis	Beauchemin et al. 2015
	miR-133	OE	Restricts CM proliferation and inhibits regeneration	Yin et al. 2012
		Depletion	Enhances CM proliferation
	miR-99/100	OE	Leads to deficiency in zebrafish heart regeneration	Aguirre et al. 2014
Transcription factors	Gata4	dn-Gata4 OE in CMs	Impairs proliferation and heart regeneration	Gupta et al. 2013
	Hand2	OE in CMs	Increases CM proliferation after injury	Schindler et al. 2014
	NF-κB	OE of dn-IκBSR in CMs	Disassembly of sarcomeres, proliferation, and induction of gata4 regulatory sequences all disrupted after injury	Karra et al. 2015