Table 1.

Extracellular signals for cardiac regeneration.

Extracellular signals	Receptor	Signal pathway	Biological effects		Clinical effects on HF patients
			In vitro	In vivo
Triiodothyronine (T3)	TR1α (thyroid hormone receptor α1)	① AMPK↑ [10] ② Regulating IGF1/IGF1-R/AKT [13] ③ ERK↑ [11]	CM growth↑ [10], CM maturation↑ [4], myofilament proteins expression↑ [12], L-type Ca2+ channel↓ [6]	CM proliferation and cardiac regeneration↑ [2], cardiac ischemia-reperfusion injury↓ [15–17], cardiac remodeling↓ [16, 18, 19]	Ventricular performance↑ [23], cardiac index↑ [24], cardiac function not improved [25],
Neuregulin-1 (NRG1)	ErbB receptor	① ERK1/2→MAPK↑ [34] ② PI3K→AKT↑ [35, 36] ③ FAK↑ [37]	CM survival↑ [36], calcium handling↑ [39], CM communication↑ [40, 41], myofibrillar structural damage in response to ErbB inhibition [38]	Development of cardiac conduction system↑ [45, 46], CM dedifferentiation and proliferation↑ [42, 43], myofilament organization↑ [44]	cardiac output↑, LVEF↑, systemic vascular resistance↓, ESV↓ EDV↓ [50, 51]
Follistatin-like 1 (Fstl1)	DIP2A (disconnected interacting protein 2 homolog A)	① AMPK↑ [57] ② p-AKT↑ [58] ③ ERK1/2↑ [55]	Cell apoptosis↓ [58]	Cardiac rupture↓ [55], CM proliferation↑, heart performance↑ [56]	N/A
TNF-related weak inducer of apoptosis (TWEAK)	Fn14 receptor	① TRAF→NF-κB↑ [68] ② ERK [70] ③ PI3K→AKT↑ [70]	CM cell cycle reentry↑ [70], cardiomyocyte proliferation↑ [69], CM-derived proinflammatory cytokines↑ [68], fibroblast proliferation and myofibroblast differentiation↑ [71]	Cardiac hypertrophy↑ [72], myocardial inflammatory responses↑ [73], heart performance↓ [74]	N/A

CM: cardiomyocyte; ↑: increase or intensify; ↓: decrease; LVEF: left ventricular ejection fraction; ESV: end-systolic volume; EDV: end-diastolic volume; N/A: not available.