Table 1.
Signaling mechanisms important in liver regeneration
| Mitogen | Cellular source | Primary or auxiliary | Function | Citation(s) |
|---|---|---|---|---|
| Hepatocyte growth factor (HGF) | Stellate cells, Kupffer cells, resident and bone marrow-derived endothelial cells, platelets | Primary | Hepatocyte proliferation, DNA synthesis | 1,8,38,a |
| Epidermal growth factor (EGF) | Brunner’s glands of duodenum, platelets | Primary | Hepatocyte proliferation, DNA synthesis | 1,8,38,a |
| Transforming growth factor α (TGFα) | Hepatocytes | Primary | Hepatocyte proliferation, perhaps at later stages, endothelial cell proliferation | 1,8,a |
| Interleukin 6 (IL6) | Kupffer cells | Auxiliary | Hepatocyte DNA/ protein synthesis, biliary epithelial cell proliferation | 1,8,a |
| Tumor necrosis factor α (TNFα) | Kupffer cells | Auxiliary | Regulates IL6 secretion | 1,8,a |
| Urokinase plasminogen activator (uPA) & metalloproteinases (MMPs) | Endothelial cells, stellate cells | Auxiliary | Remodel extracellular matrix prior to hepatocyte proliferation | 9,46,47,a |
| Wnts | Endothelial cells (Wnt2, others), Kupffer cells (unknown Wnts), Hepatocytes | Unknown | Induces β-catenin activation and in turn cyclin-D1 expression to promote hepatocyte cell cycle entry | 10–13 |
| Vascular endothelial growth factor (VEGF) | Kupffer cells | Auxiliary | Induces endothelial cell proliferation and angiogenesis | 22 |
| Interleukin 22 (IL22) & Purinergic receptor P2X1 (P2X1) | Lymphocytes | Primary and Auxiliary | Promote IL6 pathway. Also has direct mitogenic effect on hepatocytes | 29–31 |
| Interleukin 17 (IL17) | Lymphocytes | Primary and Auxiliary | Promotes hepatocyte proliferation directly and through IL6 | 32,34 |
| Interleukin 4 (IL4) | Eosinophils, NKT cells | Primary and Auxiliary | Induces FoxM1 and cyclin-B1 | 35 |
| Serotonin | Platelets | Auxiliary | Induces hepatocyte mitosis through TGFβ inhibition | 40 |
| Platelet-derived growth factor receptor β (PDGFRβ) | Stellate cells | Auxiliary | Protects liver from injury during LR | 49 |
| Angiopoietin-2 (Ang2) | Endothelial cells | Auxiliary | Downregulation during LR enables hepatocyte proliferation | 52 |
| Osteopontin | Biliary epithelial cells | Auxiliary | Activates macrophages | 58 |
| Farnesoid X receptor (FXR) | Hepatocytes | Auxiliary | Protects against bile-toxicity and promotes liver growth | 69 |
| ATP binding cassette subfamily C member 3 (Abcc3) | Hepatocytes | Auxiliary | May activate FXR and regulate hepatic bile content during LR | 71 |
| G-protein-coupled bile acid receptor 1 (TGR5) | Hepatocytes, endothelial cells | Auxiliary | Stimulates nitric oxide production from endothelial cells, protects from bile acid accumulation and stimulate LR after PHx | 72,73 |
| Purinergic receptor P2X4 | Hepatocytes | Auxiliary | Activated by ATP released after PHx, indirectly induces cyclin-D1 | 75 |
| Nitric oxide synthase (NOS) | Endothelial cells | Auxiliary | Stimulate immediate early gene expression | 76 |
| Hypoxia inducible factor 1 (Hif1α) | Hepatocytes | Auxiliary | Activates VEGF to induce angiogenesis | 77,78 |
| Downregulated miRNAs: miR-503, miR-23a, miR-150, miR-663, miR-654, miR-33 | Auxiliary | Promote cell-cycle entry | 15,17 | |
| Up-regulated miRNAs: miR-126, miR-130a, miR-20a, miR-520e, miR-330, miR-21 | Auxiliary | Promote cell-cycle entry | 15,16 | |
| lncRNA-LALR1 | Auxiliary | Regulation of cyclin-D1 via β-catenin | 18 |