|
| Factor | Origin | Target |
|
| Complete mitogens |
| HGF | Mainly stellate cells | HGF directly regulates hepatocyte DNA synthesis and cell proliferation by blinding to its receptor c-met. |
| EGF | Brunner’s gland in the duodenum | They provoke hepatocyte proliferation mainly through the Ras-MAPK signaling pathway by binding to their identical receptor and may compensate for each other to some degree in the process. |
| TGF-α | Hepatocytes |
| Auxiliary mitogens |
| Bile acids | Hepatocytes and cholangicytes | Appropriate concentration of BAs may promote liver regeneration mainly via farnesoid X receptor (FXR) signaling pathways to stimulate the expression of FoxM1b, a key regulator of cell cycle, to participate in cells proliferation [31]. |
| NE | Nerve system | NE may amplify the effect of EGF and HGF by acting on the α1-adrenergic receptor associated with Gαh, a G protein [32, 33], and besides, it could induced the expression of Smad7 to abolish activin A-induced growth inhibition of hepatocyte by activation of NF-κB [34]. |
| VEGF | Hepatocytes | VEGF family, particularly VEGF-A, is strongly upregulated in hepatocytes during the regenerative process and may facilitate proliferation of sinusoidal endothelial cells and hepatocytes 48 h following PHx [35]. |
| Insulin | Pancreatic islets | Insulin could contribute to liver regeneration despite not being a primary mitogen and its proliferative effect mainly mediated through insulin receptors (IRs) that shift to nucleus to activate inositol 1,4,5,-trisphosphate- (InsP3-) dependent Ca2+ signaling pathways [36]. |
| IGF-1 | Liver | IGF-I works as a booster to liver regeneration by upregulation of HGF and downregulation of transforming growth factor beta 1(TGF-β1), a repressor of proliferation, and decreased level of IGF-I could impair the regenerative process [37]. |
| Estrogen | Reproductive system | Estrogen has been shown to promote hepatocyte proliferation mainly through estrogen receptor alpha (ERα) [38]. Moreover, the estrogen level could be influenced by IL-6 and there may be crosstalk between estrogen signaling and IL-6 signaling pathways [39]. |
| Serotonin (5-hydroxytryptamine, 5HT) | Enterochromaffin cells | Serotonin, via HT receptor 2 (HTR2), has been reported to contribute to liver regeneration [40]. And it was found that liver regeneration would be arrested when ketanserin was administrated to block 5-HT2, a subtype of 5-HT, approximately at the G1/S transition point [41]. |
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