Advances in Translational Medicine of Liver Regeneration-Associated Regulatory Factors
HAN Jin-bin1,*, MA Cong2, SHI Yan-qiong3
1. Department of Oncology, Central Hospital of Xuhui District, Shanghai, 200031, China
2. Department of Endocrinology, Central Hospital of Xuhui District, Shanghai, 200031, China
3. Outpatient Pharmacy, Central Hospital of Xuhui District, Shanghai, 200031, China
Corresponding Author: HAN Jin-bin, E-mail: hanjinbin@gmail.com
Abstract

The liver is an important organ that has strong regeneration and defensive ability in human body. The cell types participating in liver regeneration have close association with the severity of liver injury. When the liver is in mild injury, it mainly repairs the injury through the cellular proliferation of liver parenchyma, whereas when the liver is in severe injury complicated with liver cell aplasia, the liver tissues will launch stem cell proliferative responses. Liver cells and stem cells have different responses to injury, so there may be specific regulation of signal routines and factors. Translational medicine mainly guides clinical practice through basic research, which not only promotes the development of modern medicine, but also is the strong impetus that promotes the development of modern medicine. The application of translational medicine has greatly improved the therapeutic efficacy of liver surgery, liver cancer and liver transplantation around the world. This study mainly reviewed the advances in translational medicine of liver regeneration-associated regulatory factors, hoping to provide references for the clinical diagnosis and treatment of liver diseases.

Key words: Liver regeneration ,Regulatory factors Translational medicine Tumor necrosis factor-α; Lipopolysaccharide ,Suppressor of cytokine signaling
Introduction

The liver is an important organ that has strong regeneration and defensive ability in human body. When various factors, such as trauma, surgery, infection, poisoning and necrosis, trigger liver injury, the residual liver tissues may regenerate quickly and recover to the previous volume and size so as to maintain the optimal ratio of hepatic weight and general body weight, consequently achieving the target of recovering liver function and reconstructing the structures of liver tissues. The cell types participating in liver regeneration have close association with the severity of liver injury, including fibrosis and inflammation. When the liver is in mild injury, it mainly repairs the injury through the cellular proliferation of liver parenchyma, whereas when the liver is in severe injury complicated with liver cell aplasia, the liver tissues will launch stem cell proliferative responses. Liver cells and stem cells have different responses to injury, so there may be specific regulation of signal routines and factors [1].

In recent years, translational medicine has become a hot topic in clinical studies. It is the bidirectional translation between laboratory and clinical practice, and it is the combination of theories and practice.. One of its important targets is to conduct individual therapy based on the diseases’ basic characteristics and molecular biological characteristics as well as patients’ heredity [2]. Neuman et al. [3] has found that the proposition and development of translational medicine is inevitable, and it guides clinical practice through basic research, which not only promotes the development of modern medicine, but also is the strong impetus that promotes the development of modern medicine. The application of translational medicine has greatly improved the therapeutic efficacy of liver surgery, liver cancer and liver transplantation at home [3]. Therefore, to summarize the advances in translational medicine of liver regeneration-associated regulatory factors is of great importance..

Liver Regeneration Launch-Associated Regulatory Factors

During liver regeneration, only if liver cells are competent of regenerative ability can they enter into the cell cycle. However, the expression of cell cycle-related genes is closely connected with heparin-binding epidermal growth factor receptor (HB-EGFR), transforming growth factor (TGF)-α and hepatocyte growth factor (HGF), which is also termed as the launch of liver regeneration [4].

Liver regeneration experiences multiple stages. In the early launch stage, numerous cell cycle-related genes express themselves respectively, such as interleukin (IL) and TNF-α [5]. Yoshiya et al. [6] also found that blockage of the apelin-APJ system which involved in the regulation of cardiovascular function, fluid homeostasis, inflammation, angiogenesis and the adipo-insular axis using F13A, could promote the liver regeneration in early stage after massive hepatectomy by activating Kupffer cells and increasing the levels of serum TNF-α and IL-6. Tiberio et al.[7]found that both TNF-α and IL-6 were synthesized and released by Kupffer cells, and could receive the stimulation of external environment or liver (like lipopolysaccharide) to launch the liver regeneration function, while the synthesis of liver cell DNA was inhibited after partial hepatectomy in rats lacking of IL-6 and TNF-α , which could be corrected after administration of IL-6 before surgery.

Lipopolysaccharide is an important component of congenital immune system, and it can combine with lipopolysaccharide receptors in V cells, so as to stimulate the production of TNF-α , IL-6 and inflammatory chemotactic factors, etc. [8]. Extracellular matrix (ECM) reconstruction plays an important role in the launch of liver regeneration. Zhang et al. [9] investigated the key molecular effect in impairing the regeneration of cholestatic liver in mice, and the results discovered that up-regulated ECM inflammatory chemokines and components had potential function in impairing the regeneration of cholestatic liver. When amounts of TGF-β 1and α 2-immunoglobin (Ig) released in blood are suppressed and inactivated, ECM will activate the release of HGF to change the balance of mitosis inhibitors and mitogen, thus achieving the target of liver regeneration [10]. Kaylan et al. [11] mainly identified distinct contributions of different ECM proteins and Notch ligands in the decisions of bipotential mouse embryonic liver (BMEL) progenitor cells which underlie bile duct formation and liver development as well as liver regeneration and other diseases, and concluded that combinatorial microenvironmental regulation and divergent Notch ligand function were of great importance in liver progenitor fate specification, and ECM also had effect on regulating both liver fate specification and morphogenesis.

Other factors, like β -chain protein [12] and liver cell nucleus Notch-1 intracellular structural domain, all participate in the launch process of liver regeneration. They appear about 15-30 min after partial hepatoectomy, but are poor in response to liver regeneration because their expression is easy to be interrupted by ribonucleic acid (RNA) [13].

Liver Regeneration Routine-Associated Regulatory Factors
Cytokine-dependent routine factors

Forbes et al. [14]indicated that liver regeneration had two routines, cytokine-dependent and non-cytokine-dependent routine, which involved large amount of associated proteins. The completion of cytokine-dependent routine mainly depends on the involvement of TNF-α , IL-6 and other cytokines (like IL-1, etc.) [15]. IL-6 combines with its receptor IL-6R, whereas IL-6R combines with 2 sub-units of glycoprotein (GP), which can activate the activity of tyrosine kinase (JAK). The activated JAK can activate the signal transduction factors and activating transcription factor-3 (STAT-3) through phosphorylation, and the activated STAT-3 in turn can change the location of nucleus and activate the expression and transcription of target genes. Meanwhile, the complexes of GP-130 and IL-6R (GP-130-IL-6R) can also give rise to cascade responses by revitalizing mitogen-activated protein kinase (MAPK), so as to promote the proliferation of liver cells [16]. At present, the defined mechanism is still unclear. But it has been proved that Src homology 2 domain (SH2) is capable of activating NV0 structural domain containing JAK and improving the release of growth factor receptor bound protein (GRB) 2-SOS. And then, the activated 2-SOS can activate extracellular signal-regulated protein kinase Ras-MAPK-ERK by revitalizing Ras system [17]. It follows that in liver regeneration, signal pathways of MAPK and STAT-3 which are inevitable for cell cycle transferring from stage G1 to stage S can be activated by IL-6 through GP-130-IL-6R, which can strengthen and promote the transcription and expression of protooncogenes in cell cycle progress, and the increased cell cycle proteins can promote cells to enter into stage S, thus finishing a complete cell replicative cycle [18].

After partial hepatectomy, another normal cellular proliferative response is TNF-α signal. TNF-α can stimulate the continuous secretion of IL-6, and activate the transcription of IL-6 by up-regulating the expression of transcription factor-κ B signal, so as to increase the expression of IL-6. In addition, TNF-α and IL-6 can jointly correct the DNA defect in TNF-R1 gene-deleted mice after hepatectomy. However, Ji et al. [19] found that IL-6 could promote the proliferation of oval cells and liver regeneration, but TNF-α /TNF receptor-1(TNFR1) did not have this function.

In the early liver regeneration, negative regulatory mechanism can induce multiple profilins, including plasminogen activator inhibitor (A1), TGF-β , p27, suppressor of cytokine signaling (SOCS)-3 and other dependent inhibitors, which can reduce the expression of STAT-3 and inhibit IL-6 signal transduction pathways [20].

Non-cytokine (growth factor)-dependent routine factors

In liver regeneration, non-cytokine-dependent routines can notably promote cell proliferation and receive the regulation of mitogens and growth factors, such as EGFR and HGF, as important somatomedins, can drive the cell cycle process during liver regeneration [21].

HGF is mainly produced by non-apenchymal cells of the liver and other tissues (especially stellate cells), and it can maintain the growth and function of liver cells via autocrine and paracrine. It can regulate the cellular morphology, mitosis and amitosis of liver cells, and is a strong differentiation- and proliferation-promoting agent for the culture of liver cells. It has an important role in cell survival, proliferation, morphogenesis and motility. After liver injury or partial hepatectomy, pro-HGF or HGF precursor will be quickly activated by protease 1 urokinase type plasminogen activator and its effector urokinase type plasminogen, and HGF can activate signal pathways containing phosphatidylinositol-3-hydroxylase (PI3K), extracellular signal-regulated kinase 1/2 (ERK), human serine/threonine kinase and S6 kinase by combining with its receptor c-Met, so as to promote the regeneration and repair of liver cells [22]. Additionally, HGF/C-Met signals can also protect the liver and effectively prevent liver cell apoptosis. Sasturkar et al. [23] evaluated the levels of biological markers of liver regeneration in healthy donors who underwent right lobe donor hepatectomy for living donor liver transplantation, and the results showed that HGF, TNF-α , IL-6 and TPO increased evidently after surgery, indicating that HGF, TNF-α , IL-6 and TPO participated in the early stage of liver regeneration. Guo et al. [24] evaluated the influence of sequential transcatheter arterial chemoembolization (TACE) and portal vein embolizations (PVE) on rabbit VX2 liver regeneration and liver carcinoma, and the results displayed that the level of TNF-α , IL-6 and HGF was the highest in TACE+PVE group, which might be the reason why TACE+PVE could induce the strongest liver regeneration than TACE or PVE alone.

EGFR-combined ligand families include TGF-α , EGF, regulatory protein (AR) and heparin-connecting EGF (HB-EGF). EGF, as a mitogenic factor for the culture of liver regeneration, can induce the differentiation and proliferation of liver cells after being injected into healthy whole animals. Although EGF will be absorbed and used gradually by the liver gradually after passing portal veins, its concentration in portal vein still cannot be measured after partial hepatectomy [25]. EGFR is a primary participant in regulating liver regeneration. In the liver, the primary effect of TGF-α mRNA is to stimulate the differentiation and proliferation of liver cells, but its expression is relatively low in normal livers. After partial hepatectomy, TGF-α mRNA expression increases gradually [26]. Liver cells proliferate more actively and may develop into cancer in transgenic mice with over-expressed TGF-α . However, TGF-α gene-deleted mice do not have liver regeneration defect, which may be closely associated with the partial reduplication among EGF familial ligands [27].

Interaction factors between cytokine-dependent and non-cytokine-dependent routines

In liver regeneration, cytokine-dependent and non-cytokine-dependent routine can jointly guide the injury repair and regeneration after hepatectomy through the interaction of common signal transduction molecules, such as transcription factors (AP-1 and C/EBPβ ), ERKHE, JNK and other molecules like insulin-like growth factor binding protein-1 (IGFBP1) [28].

Cytokines (like TNF-α ) activating metalloprotease (MMPs) is an important connection between cytokines and growth factors. After partial hepatectomy, numerous MMPs still have persistently strong activity [29], in which TGF-α invertase (TACE, also termed as ADAM17) is one of the critical enzymes. TNF-α can activate TACE, while the latter can anchor TGF-α precursor on cell membrane. Moreover, TGF-α can stimulate the differentiation and proliferation of liver cells after activating and releasing EGFR.

Liver regeneration termination-associated regulatory factors

Liver size is easily be limited and is in close correlation with the requirement of human body to liver function. TGF-β and its family members are known as intra-hepatic anti-hyperplasia factors. TGF-β is mainly produced by Kupffer’ s cells. Martino et al.[30] investigated the mechanism of pentoxifylline (PTX) in improving liver regeneration, and they found that the levels of serum TNF-α and IL-6 increased notably 2 h and 6 h after hepatectomy while TGF-β 1 gene expression showed a significant decrease in liver, illustrating that PTX could improve liver regeneration by down-regulating TGF-β 1 gene expression and production of TNF-α . These findings demonstrated that the increase of TGF-β might inhibit the liver regeneration. Activin can inhibit the mitosis of liver cells. In the liver regeneration, if cell receptor level decreases, corresponding signal effect will decrease too. Once the liver regeneration is terminated, its cell receptor level will be re-repaired [31]. ECM can also inhibit the liver cell proliferation and enhance the liver differentiation [32]. In addition, Klaaset al.[33] identified the shifts in ECM composition after treatment with DDC or CCl4 using a proteomics-based approach, and then studied their influence on proliferation of liver cells by combining cell culture and biophysical methods, and the results suggested remarkable alternations in structural components and non-structural proteins of ECM, and the alternations in ECM components were nonhomogenous and varied between pericentral and periportal areas, demonstrating that selected ECM components had differential ability in regulating the proliferation of biliary cells and hepatocytes, and a coordinated ECM remodeling was efficient in liver regeneration.

SOCS is an important negative instrumentality in cytokine signal transduction, which can inhibit the phosphorylation of STAT protein tyrosine. SOCS interacts with phosphorylated JAK to inhibit the activation of STAT3. Drucker et al. [34]suggested that intra-hepatic IL-6 signal could promote the rapid expression of SOCS, and this process was closely associated with the reduced expression of phosphorylated STAT3. Lee et al. [35] revealed that hypoxemia could markedly increase the mRNA expression of adipose-derived stem cells (ASCs) mediators, including HGF, VEGF, TNF-α and IL-6, and the liver regenerative effects of hypoxic-conditioned media (HCM) was mediated by uninhibited and persistent expression of phospho-signal transducer and STAT3 in the liver, which results from the increase of SOCS3 expression, indicating that treatment with the medium (like HGF, VEGF, TNF-α and IL-6, etc.) from hypoxic-preconditioned ASCs could enhance the liver regeneration in partially hepatectomized mice.

Hippo kinase signal cascade, as a growth-inhibition pathway, can antagonize transcriptional coactivator YAP (Yes-associated protein), consequently controlling the proliferation of liver cells. Liver cells in transgenic mice with over-expressed YAP can unlimitedly differentiate and proliferate, which may trigger the proliferation and canceration of numerous liver cells, whereas Hippo can recover the normal liver size by inhibiting the over-expressed YAP. The Hippo pathway, originally identified in Drosophila through a genetic approach, was found to be an evolutionarily conserved signaling module which exerts a great effect on the control of liver size and tumorigenesis by regulating YAP activity and expression that controls tissues’ growth [36]. Hippo signaling pathway, as an important regulator for cellular proliferation and organ size, is essential for the cell fate determination in the liver and is required to maintain the differentiated hepatocytic state [37, 38]. Over-expressed YAP led to liver enlargement and hepatocyte hyperproliferation [39], while inactivation of YAP brought about loss of hepatocytes and biliary epithelial cells, eventually causing liver damage [40].

Conclusion

Effective liver regeneration process involves the activation of more than 100 genes and participation of regulatory factors, and the mechanism of liver cell regeneration is a complicated biological topic. At present, amount of cytokines (like IL-6 and TNF-α ), growth factors (like hepatocyte growth cells and TGF-α ) and various cells act on liver cells through autocrine and paracrine to jointly complete the liver regeneration process [41]. The further studies in this filed can be beneficial to seeking better therapeutic methods for liver diseases so as to improve the prognosis of patients with advanced liver diseases.

Acknowledgments

This study was supported by National Natural Science Foundation of China (No.: 8473498).

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