Table 2:
Epicardial signals relevant to heart regeneration or repair
| Signaling | Models | Gene induction domains upon injury * | Functional evidence in heart regeneration | References |
|---|---|---|---|---|
| Retinoic Acid (RA) | Zebrafish | raldh2: epicardium, endocardium | Expression of a dominant-negative RARα impairs CM proliferation and heart regeneration. | (Kikuchi et al., 2011b; Lepilina et al., 2006) |
| Mouse |
Raldh2: epicardium (RXRα: epicardium) |
(Limana et al., 2010; Merki et al., 2005; Porrello et al., 2011; van Wijk et al., 2012) | ||
| Fibroblast Growth Factors (FGFs) | Zebrafish |
fgf17b: CMs fgfr2 and fgfr4: EPDCs |
Expression of a dominant-negative fgfr1 blocked epicardial cell EMT, coronary neovascularization, and muscle regeneration. | (Lepilina et al., 2006) |
| Rat |
FGF1: inflammatory cells and fibroblast-like cells FGF2: endothelial cells, CM FGFR: CM |
(Zhao et al., 2011) | ||
| Transforming Growth Factor-beta (TGFβ) | Zebrafish |
tgfb1, 2, and 3: epicardial cells, fibroblasts and CMs Alk5b: CMs and fibrotic cells pSmad3: CMs and non-CMs in the infarct area |
Inhibition of the TGFβ pathway impaired ECM deposition, CM proliferation, and heart regeneration. | (Cao et al., 2016a; Chablais and Jazwinska, 2012; Choi et al., 2013) |
| Rat, Pig | Tgfb1, 2, and 3: infarcted myocardium | (Deten et al., 2001; Hao et al., 1999; Vilahur et al., 2011) | ||
| Notch | Zebrafish |
notch1a, notch1b, and notch2: endocardium notch1a and notch2: epicardium notch1b, notch2, notch3, and Dll4: endocardium |
Suppression of Notch signaling decreased CM proliferation, induced scar formation and impaired heart regeneration. Overexpression of NICD suppressed CM proliferation and heart regeneration in the resection model while augmenting CM proliferation in the cryoinjury model. | (Zhao et al., 2014) (Munch et al., 2017) |
| Mouse | Notch activity reporter: CMs, epicardial cells/EPDCs NICD1: CM |
Overexpression of NICD1 in adult CM increased the number of Ki67+ CMs. | (Kratsios et al., 2010; Russell et al., 2011) | |
| NF-κB | Zebrafish |
nfkb1, nfkbiaa and nfkbiab: CMs |
NF-κB blockade in CMs impaired epicardial cell infiltration into the wound, CM proliferation and heart regeneration. | (Karra et al., 2015) |
| Platelet-Derived Growth Factors (PDGFs) | Zebrafish |
pdgfrβ: epicardium and fibrin clots pdgfb: thrombocytes at the wound site |
Pharmacological inhibition of PDGF decreased epicardial cell proliferation and coronary blood vessel formation. | (Kim et al., 2010) |
| Mouse |
PDGFB, PDGFRα and PDGFRβ: the infarct phosphorylated PDGFRβ: perivascular cells in the infarct |
PDGFRβ blockade impaired collagen deposition and vasculature maturation in the infarct. PDGFRα blockade impaired collagen deposition. | (Zymek et al., 2006) | |
| Wnt | Mouse |
Wnt1: epicardium, cardiac fibroblasts Wnt10b: CMs in the peri-infarct area. |
Deleting β-catenin in the epicardium disrupted epicardial cell expansion and EMT and decreased heart function after MI; deleting β-catenin in cardiac fibroblasts led to acute cardiac dilatation and cardiac dysfunction. Wnt10b overexpression increased neovascularization of scar tissue and attenuated fibrosis. |
(Duan et al., 2012) (Paik et al., 2015) |
| Hedgehog (Hh) | Zebrafish |
shha: epicardial tissue adjacent to and within the injury site ptch2: CMs in the injury site |
Pharmacological inhibition of Hh or epicardial specific deletion of shha decreased CM proliferation, while an Hh agonist increased proliferation. | (Choi et al., 2013; Sugimoto et al., 2017) |
| Insulin-like Growth Factor (IGF) | Zebrafish |
Igf2b: epicardium and endocardium igfr1: CMs at the injury site |
Expression of a dominant-negative igf1r impaired CM proliferation and heart regeneration. Inhibiting Igf decreased CM proliferation, an Igf agonist increased CM proliferation. |
(Huang et al., 2013) (Choi et al., 2013) |
| Mouse | IGF1R: epicardium | Inhibition of IGF1R in Wt1+ lineages after MI reduced adipogenic differentiation. | (Zangi et al., 2017) | |
| BMP | Zebrafish |
bmp2b, bmp7: epicardium, endocardium bmpr1aa: wound border zone id2b: endocardium pSmad1/5/8: CM |
Overexpression of noggin3 decreased CM dedifferentiation and proliferation, and increased scar tissue, while overexpression of bmp2b did the opposite. bmpr1aa mutants had fewer CM proliferation. | (Wu et al., 2016) |
| Mouse |
Bmp4: whole heart (RT-PCR) |
Overexpression of noggin, pharmacological inhibition of BMP, or using the Bmp4+/− mice demonstrated reduced infarct size and CM apoptosis in a MI and reperfusion mouse model. | (Pachori et al., 2010) | |
| Hippo/Yap | Mouse | (Yap, Taz, Tead1–3, Lats1 and Lats2 are expressed in the proepicardium and epicardium during development.) | Deficiency in epicardial Yap/Taz caused pericardial inflammation, myocardial fibrosis, cardiomyopathy, and death after MI. Deletion of Lats1/2 in embryonic (E11.5) epicardium reduced the epicardial differentiation to fibroblast. |
(Lin and Pu, 2014; Ramjee et al., 2017) (Xiao et al., 2018) |
| Chemokines (Cxcl12a-Cxcr4b) | Zebrafish |
cxcl12a: epicardium cxcr4: CMs |
An antagonist that blocks Cxcr4 function disrupted heart regeneration by impairing CM migration to the injury site. | (Itou et al., 2012) |
| Neuregulin 1 (Nrg1) | Zebrafish | nrg1: epicardial-derived perivascular cells, regulatory T cells | Overexpression of Nrg1 promotes CM proliferation. | (Gemberling et al., 2015; Hui et al., 2017; Kang et al., 2016) |
| Mammals | Nrg1: endothelial cells | Overexpression of Nrg1 promotes proliferation of mononucleated CMs. | (Bersell et al., 2009; Parodi and Kuhn, 2014) | |
| Follistatin-like-1 (FSTL1) | Mouse, swine | FSTL1: CMs (FSTL1 is expressed in the epicardium in uninjured hearts, and is induced in CMs and decreased in the epicardium.) FSTL1: fibroblast in the infarct |
Application of epicardially derived FSTL1 stimulated CM proliferation, diminished infarct size and improved heart function after MI. Intravenous delivery of FSTL1 protein or adenovirus-driven FSTL1 expression before MI reduced the infract size. FSTL1 promotes cardiac fibroblast activation and protects the heart from rupture |
(Wei et al., 2015) (Ogura et al., 2012; Oshima et al., 2008) (Maruyama et al., 2016) |
| Thymosin β4 (Tβ4) | Mouse | Tβ4: epicardium, endocardium and capillaries | Treatment with Tβ4 prior to MI activated the adult epicardium, stimulated vascular growth, and induced epicardial to CM differentiation in very rare cases. Treatment with Tβ4 after MI increased the thickness of the epicardium and coronary capillary density. Deletion of Tβ4 in heart diminished neovascularization in the infarct border zone. | (Bock-Marquette et al., 2009; Dube et al., 2017; Smart et al., 2011; Smart et al., 2007; Zhou et al., 2012) |
| Caveolin 1 (cav1) | Zebrafish | (cav1 is expressed in epicardial cells, EPDCs, and coronary vascular endothelial cells.) | cav1 deletion decreased CM proliferation and impaired heart regeneration. | (Cao et al., 2016a) |
*
Non-injury related expression and downregulation are listed in brackets.