Research progress of liver regeneration after hepatectomy for hepatocellular carcinoma / 中华肝胆外科杂志

Liver is an organ with strong regenerative potential. After trauma, infection, surgery and so on, it will initiate a series of regulation for orderly regeneration to rapidly restore liver function and liver volume and thus maintain normal physiological function. This article summarizes the process of liver regeneration after hepatectomy, the evaluation methods for liver regeneration and the factors affecting liver regeneration, so as to provide references for clinical precision liver surgical treatment.

The effect of ALPL on liver regeneration after partial hepatectomy in mice / 西安交通大学学报(医学版)

【Objective】 To observe the role of liver/bone/kidney alkaline phosphatase gene (ALPL) in liver regeneration following 70% hepatectomy (partial hepatectomy, PH). 【Methods】 A knock-out mouse model (ALPL+/-) was established, and a 70% hepatectomy was performed. Changes in liver weight and liver function were measured at PH 1 day, PH 3 day, and PH 7 day (PH1d、PH3d、PH7d) after surgery. In addition, cell proliferation, hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) were performed by Western blotting, immunofluorescence staining, and enzyme linked immunosorbent assay. 【Results】 ALPL knockout mice at PH7d exhibited a lower ratio of liver/total body weight than normal control mice. An analysis of liver function showed no significant difference between the ALPL knockout group and the WT (ALPL+/+) group when the ALPL gene was deleted. While Ki67 staining and PCNA analysis indicated that liver cell proliferation was decreased in ALPL+/- mice at PH1d and increased at PH7d compared to that in ALPL+/+group. Additionally, knockouts of ALPL decreased serum and liver HGF and VEGF levels at PH1d compared to WT controls, but increased at PH7d. 【Conclusion】 The knockout of ALPL leads to a delayed liver regeneration following hepatectomy, which provides theoretical support for exploring the mechanisms underlying liver regeneration after hepatectomy.

Expression and significance of response gene to complement 32 in liver regeneration after partial hepatectomy in mice / 临床肝胆病杂志

ObjectiveTo investigate the expression and role of response gene to complement 32 （RGC32） in liver regeneration after partial hepatectomy （PH）. MethodsA total of 42 male C57BL/6 mice， aged 10 weeks， were randomly divided into control group， postoperative day 1 group （1－d group）， postoperative day 2 group （2－d group）， postoperative day 4 group （4－d group）， postoperative day 6 group （6－d group）， postoperative day 8 group （8－d group）， and postoperative day 10 group （10－d group）， with 6 mice in each group. In the control group， the complete liver of the mice was resected for weighing and photography as the normal control group （sham group）； further， the left and middle lobes of the liver were resected for weighing and photography as the surgical control group （0－day group）； the sham group and the 0－day group shared the same group of mice. After successful modeling by PH， the mice were sacrificed on days 1， 2， 4， 6， 8， and 10 after surgery， and the liver was collected to measure the change in size. HE staining and oil red O staining were used to evaluate liver histomorphological changes； serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were measured to evaluate the changes in liver function； immunohistochemical staining was used to measure the expression of proliferating cell nuclear antigen （PCNA） and Ki67 and analyze the change in cell proliferation during liver regeneration； quantitatie real－time PCR and immunohistochemical staining were uused to measure the expression and subcellular distribution of RGC32 during liver regeneration； EdU cell proliferation assay was used to analyze the effect of RGC32 overexpression or knocknout on hepatocyte proliferation in L02 cells. For continuous data， comparison between multiple groups was made by analysis of variance， and further pairwise comparisons were conducted using the LSD－t test. The independent samples t－test was used for comparison of continuous data between two groups. A Pearson correlation analysis was performed. ResultsThe liver gradually enlarged after PH， and the liver/body weight ratio rose to the peak from days 0 to 6， with significant differences between different time points （all P<0.05）， while there was no significant change in liver size from days 6 to 10. The number of liver lipid droplets significantly increased after PH surgery and gradually decreased with liver regeneration， with a significant difference between the portal vein region and the central vein region （all P<0.05）. Compared with the sham group， the 1d group had significant increases in the serum levels of ALT and AST （all P<0.05）， which gradually returned to the levels of the sham group on day 6 and day 2 after surgery， respectively （P>0.05）. Immunohistochemical staining showed that there were rapid increases in the numbers of PCNA－ and Ki67－positive liver parenchymal cells after PH surgery， with the highest numbers of 86±5 and 89±5， respectively， on day 2， which then gradually decreased； however， there were gradual increases in the numbers of PCNA－ and Ki67－positive nonparenchymal cells， with the peak numbers of 34±5 and 25±3， respectively， on day 6， which then gradually decreased. The total expression of RGC32 increased to the highest level on day 2 after PH surgery and then gradually decreased， and the changing trend of RGC32 expression in cytoplasm was consistent with that of total RGC32 expression； however， the expression of RGC32 in nucleus decreased to the lowest level on day 2 after PH surgery and then increased gradually. The correlation analysis showed that the expression of RGC32 in nucleus was negatively correlated with the proliferation of liver parenchymal cells （R2=0.308 3， P=0.016 7）， and the expression of RGC32 in cytoplasm was positively correlated with the proliferation of liver parenchymal cells （R2=0.808 6， P<0.000 1）. Cell experiments showed that compared with the control group， the EdU－positive rate was reduced by 15.6% after RGC32 overexpression （P<0.01） and was increased by 19.2% after RGC32 knockdown （P<0.01）. ConclusionLiver parenchymal cells and nonparenchymal cells show asynchronous proliferation and participate in liver regeneration together. During liver regeneration after hepatectomy， there are differences in the expression of RGC32 between nucleus and cytoplasm， and RGC32 in nucleus may inhibit hepatocyte proliferation.

Clinical efficacy of TACE combined with PVE versus percutaneous microwave ablation liver partition with PVE for planned hepatectomy for hepatocellular carcinoma with insufficient remnant liver volume / 中华肝胆外科杂志

Objective:To evaluate the safety and clinical efficacy of transcatheter arterial chemoembolization (TACE) combined with portal vein embolization (PVE) and percutaneous microwave ablation liver partition with PVE for planned hepatectomy in patients with hepatocellular carcinoma (HCC) with insu-fficient remnant liver volume.Methods:The clinical data of 51 patients with initially unresectable HCC due to insufficient remnant liver volume admitted to Zhejiang Provincial Tongde Hospital and Zhejiang Provincial People’s Hospital from January 2014 to December 2021 were retrospectively analyzed, including 37 males and 14 females, aged (56.7±11.2) years old. Patients were divided into two groups according to the treatment prior to hepatectomy: percutaneous microwave ablation liver partition combined with PVE (AP group, n=12) and TACE with PVE (TP group, n=39). Patients who successfully underwent planned hepatectomy in the above two groups were marked as resectable AP group ( n=10) and the resectable TP group ( n=29), respectively. Clinical data including the waiting time for surgery and the incidence of complications were analyzed. Patients were followed up by telephone or outpatient review. Kaplan-Meier and log-rank analysis were used for survival comparison. Results:The FLR growth rate was higher in AP group [76.5% (65.3%, 81.6%)] than that in TP group [31.4% (28.2%, 41.9%), P<0.01]. The waiting time for planned hepatectomy in the resectable AP group was 12.0 (11.3, 14.5) d, shorter than that in the resec-table TP group [21.0 (15.0, 29.0) d, P<0.05]. The incidence of postoperative complications was higher in the resectable AP group than that in the resectable TP group [80.0% (8/10) vs. 27.6% (8/29), P<0.05]. There was one perioperative death in the resectable AP group. The survival rate after PVE was lower in AP group than that in TP group, and the survival rate after hepatectomy was also lower in the resectable AP group than that in the resectable TP group (all P<0.05). Conclusion:For HCC patients with insufficient FLR, TACE combined with PVE is a safe and effective method for enlargement of liver remnant, whereas percutaneous microwave ablation liver partition with PVE showed a poor prognosis, despite the higher rate of FLR enlargement and shortened the waiting time for planned hepatectomy.

Clinical efficacy of portal vein embolization with different embolization materials in patients with initially unresectable hepatocellular carcinoma / 中华肝胆外科杂志

Objective:To study the clinical effects of portal vein embolization (PVE) with N-butyl cyanoacrylate copolymer (NBCA) and with gelatin sponge (GS) as embolization materials in patients with initially unresectable hepatocellular carcinoma (HCC).Methods:Clinical data of 90 patients with initial unresectable HCC who underwent PVE treatment at the Third Affiliated Hospital of Naval Medical University from November 2014 to April 2020 were included. There were 77 males and 13 females, aged 48 (25, 67) years old. Patients were divided into two groups according to the embolization materials selected in PVE: NBCA group ( n=60) and GS group ( n=30). Forty-eight and 18 patients finally underwent secondary hepatectomy in NBCA group (resectable NBCA group) and GS group (resectable GS group), respectively. Clinical data including future liver remnant (FLR) growth rate and secondary hepatectomy rate were analyzed. Survivals after hepatectomy was followed up by telephone, WeChat, and outpatient review. Results:The secondary hepatectomy rate in NBCA group was higher than that in GS group [80%(48/60) vs. 60%(18/30), P=0.043]. The waiting time from primary intervention to secondary hepatectomy in resectable NBCA group was 15 (7, 96) d, which was shorter than that in resectable GS group [40 (28, 118) d, P<0.001]. The FLR growth rate of resectable NBCA group was 9.03 (1.24, 29.64) ml/d, which was faster than that in resectable GS group [3.76 (0.08, 8.03) ml/d, P<0.001]. The recurrence-free survival (RFS) rates of patients in resectable NBCA group were 69.1%, 62.0% and 44.7% at 1, 2 and 3 years after surgery, and the overall survival (OS) rates were 76.4%, 69.5% and 59.6%, respectively. The RFS rates of patients in resectable GS group were 60.6%, 48.5% and 35.4% at 1, 2 and 3 years after surgery, and the OS rates were 66.7%, 60.6% and 42.4%, respectively. There were no significant differences in RFS and OS between two groups (all P>0.05). Conclusions:PVE with NBCA and GS as embolization material showed good efficacy in patients with initially unresectable HCC. The FLR growth rate and secondary hepatectomy rate of patients using NBCA were better than those of patients using GS.

Research progress of accelerated liver regeneration induced by associating liver partition and portal vein ligation for staged hepatectomy / 中华肝胆外科杂志

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can induce accelerated regeneration of future liver remnant (FLR) and provide the opportunity of radical resection for previously inoperable patients with liver cancer, which has been considered to be one of the most important breakthroughs in liver surgery during the 21st century. It is of great significance to fully understand the mechanism of accelerated liver regeneration induced by ALPPS. This article comprehensively reviews the research progress in this field during the past 10 years.

Potential value of mesenchymal stem cells and their derivatives in repairing donor liver / 器官移植

In recent years, organ transplantation has developed rapidly in China, whereas the proportion of supply and demand of organs for donation is severely unbalanced. To resolve the shortage of donor livers, repairing extended criteria donor liver and improving the quality of donor liver are critical research directions. Mesenchymal stem cell (MSC) is a category of stem cells with self-renewal and differentiation potential, which possess the functions of immunomodulation and tissue repair. The derivatives of MSC have the advantages of low immunogenicity and high biocompatibility, which have been widely applied in the treatment of multiple diseases. In this article, research progress on the role of MSC, exosomes and extracellular vesicles in alleviating liver steatosis, repairing ischemia-reperfusion injury and promoting the regeneration of small-for-size liver allograft was reviewed, and the feasibility and safety of MSC and the derivatives in repairing donor liver were summarized, aiming provide novel ideas for repairing marginal donor liver and enhancing the quality of liver allograft.

Effect of Toll-like receptor 4 on liver regeneration during acetaminophen-induced liver injury in mice / 临床肝胆病杂志

Objective To investigate whether Toll-like receptor 4 (TLR4) inhibition affects liver regeneration during acetaminophen (APAP)-induced liver injury in mice, as well as the mechanism of TLR4 involved in liver regeneration. Methods A total of 78 male CD-1 mice were divided into nine groups using a random number table, i.e., three control groups (normal control group, solvent control group, inhibitor control group) with 6 mice in each group and six experimental groups (APAP 24-hour group, TAK-242+APAP 24-hour group, APAP 48-hour group, TAK-242+APAP 48-hour group, APAP 72-hour group, TAK-242+APAP 72-hour group) with 10 mice in each group. The mice in the experimental groups were given a single dose of intraperitoneally injected APAP (300 mg/kg), and TAK-242 was intraperitoneally injected at a dose of 3 mg/kg at 3 hours before APAP administration. Serum and liver tissue samples were collected at different time points. The biochemical method was used to measure the serum level of alanine aminotransferase (ALT); HE staining was used to observe liver pathological changes; RT-PCR, Western blot, and immunohistochemistry were used to measure the expression levels of Cyclin D1, PCNA, Ki-67, STAT3, and p-STAT3. The t -test was used for comparison of normally distributed continuous data between two groups; a one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t -test was used for further comparison between two groups. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups, and the Kruskal-Wallis H test was used for comparison between multiple groups and further comparison between two groups. Results Compared with the normal control group, the APAP 24-hour and 48-hour groups had a significantly higher serum level of ALT (both P < 0.05), and the TAK-242+APAP 24-hour and 48-hour groups had a significantly higher serum level of ALT than the APAP group at the same time point (both P < 0.05). HE staining showed typical central lobular necrosis in the liver of APAP-treated mice, and the TAK-242+APAP 24-hour and 48-hour groups had a significantly larger necrotic area than the APAP group at the same time point (both P < 0.05). RT-PCR, Western blot, and immunohistochemistry showed that the TAK-242+APAP 24-hour, 48-hour, and 72-hour groups had significantly lower mRNA and protein expression levels of Cyclin D1 than the APAP group at the same time point (all P < 0.05); the TAK-242+APAP 24-hour, 48-hour, and 72-hour groups had a significantly lower mRNA expression level of PCNA than the APAP group at the same time point (all P < 0.05), and the TAK-242+APAP 24-hour and 48-hour groups had a significantly lower protein expression level of PCNA than the APAP group at the same time point (all P < 0.05); the TAK-242+APAP 24-hour and 72-hour groups had a significantly lower mRNA expression level of Ki-67 than the APAP group at the same time point (all P < 0.05), and the TAK-242+APAP 24-hour, 48-hour, and 72-hour groups had a significantly lower protein expression level of Ki-67 than the APAP group at the same time point (all P < 0.05). In addition, the TAK-242+APAP 24-hour and 48-hour groups had a significantly lower phosphorylation level of STAT3 than the APAP group at the same time point (both P < 0.05). Conclusion TLR4 may promote liver regeneration by increasing the phosphorylation level of STAT3 during APAP-induced liver injury in mice.

Human umbilical cord mesenchymal stem cell-derived extracellular vesicles enhance the regenerative capability of fibrotic liver / 器官移植

Objective To investigate the role of human umbilical cord mesenchymal stem cell-derived extracellular vesicle (hUC-MSC-EV) in the regeneration of fibrotic liver. Methods C57BL/6 mice were randomly divided into the 70% normal liver resection group (Oil+PHx group), 70% liver fibrosis resection group (CCl4+PHx group) and 70% liver fibrosis resection+mesenchymal stem cell-derived extracellular vesicle (MSC-EV) treatment group (CCl4+PHx+MSC-EV group), with 8 mice in each group. LX-2 cell lines were assigned into the phosphate buffer solution (PBS) group, transforming growth factor (TGF)-β group and TGF-β+MSC-EV group. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in mice after partial liver resection were detected in each group. The expression levels of liver fibrosis and proliferation-related parameters were analyzed in each group. The messenger RNA (mRNA) expression levels of epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in LX-2 cells were detected in each group, and their effects on HGF expression in mouse liver were observed. Results Compared with the Oil+PHx group, the serum levels of AST, ALT and LDH were up-regulated, and the degree of fibrosis was more severe, the positive area of Sirius red and α-smooth muscle actin (α-SMA) staining was larger, and the expression level of α-SMA protein was up-regulated in the CCl4+PHx group. Compared with the CCl4+PHx group, the serum levels of AST, ALT and LDH were decreased, the degree of fibrosis was slighter, the positive area of Sirius red and α-SMA staining was decreased, and the expression level of α-SMA protein was down-regulated in the CCl4+PHx+MSC-EV group, and the differences were statistically significant (all P < 0.05). Compared with the Oil+PHx group, the protein expression levels of Ki67 and proliferating cell nuclear antigen (PCNA) were lower in the CCl4+PHx group. Compared with the CCl4+PHx group, the protein expression levels of Ki67 and PCNA were increased in the CCl4+PHx+MSC-EV group, and the differences were statistically significant (all P < 0.05). Compared with the PBS group, the expression level of CollagenⅠ mRNA in LX-2 cells was increased, the expression level of α-SMA protein was up-regulated and the expression level of HGF protein was decreased in the TGF-β group. Compared with the TGF-β group, the expression level of CollagenⅠ mRNA in LX-2 cells was decreased, the expression levels of HGF mRNA and protein were increased, and the expression level of α-SMA protein was decreased in the TGF-β+MSC-EV group, the differences were statistically significant (all P < 0.05). The expression level of HGF protein in the CCl4+PHx group was lower than that in the Oil+PHx group, whereas the difference was not statistically significant (P > 0.05). The expression level of HGF protein in the CCl4+PHx+MSC-EV group was higher than that in the CCl4+PHx group, and the difference was statistically significant (P < 0.05). Conclusions The regenerative capacity of fibrotic liver is weaker than that of normal liver. hUC-MSC-EV may alleviate liver fibrosis and improve liver regeneration by promoting HGF secretion from actived hepatic stellate cells and effectively enhancing the regenerative capacity of fibrotic liver.

Application of single cell sequencing technology in liver regeneration / 中华消化外科杂志

The liver is a highly proliferative organ. As the liver injured, the hepatocytes can quickly enter the cell cycle to restore the volume and function of liver. Liver regeneration involves complex processes that depend on the interaction of many different cell types. As limited by the average cell change level in tissues, traditional sequencing methods can only acquire the average genetic information reflecting dominant cell subpopulations, but ignore the secondary cell subpopu-lations, which leads to the loss of cellular heterogeneity information. Single-cell sequencing tech-nology can analyze the biological behavior of single cell, which helps to better understand the distri-bution, interaction and cell heterogeneity of different cells during liver regeneration. The authors review the application of single cell sequencing technology in liver regeneration.

Liver cell therapies: cellular sources and grafting strategies / 医学前沿

The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver's cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.

Liver regeneration after extensive hepatectomy in rats: effect of preoperative chemotherapy with intravenous 5-fluorouracil

Purpose: To evaluate the effect of preoperative intravenous chemotherapy with 5-fluorouracil on liver regeneration in an experimental model of major hepatectomy in rats. Methods: Wistar rats were divided into two groups of 20 animals each and submitted to 70% hepatectomy 24 h after intravenous injection of 5-fluorouracil 20 mg/kg (fluorouracil group, FG) or 0.9% saline (control group, CG). After hepatectomy, each group was subdivided into two subgroups of 10 animals each according to the day of sacrifice (24 h or 7 days). Liver weight during regeneration, liver regeneration rate using Kwon formula, and the immunohistochemical markers proliferating cell nuclear antigen (PCNA) and Ki-67 were used to assess liver regeneration. Results: At early phase (24 h after hepatectomy) it was demonstrated the negative effect of 5-fluorouracil on liver regeneration when assessed by Kwon formula (p < 0.0001), PCNA analysis (p = 0.02). With regeneration process complete (7 days), it was possible to demonstrate the sustained impairment of chemotherapy with 5-fluorouracil on hepatocytes regeneration phenomenon when measured by Kwon formula (p = 0.009), PCNA analysis (p = 0.0001) and Ki-67 analysis (0.001). Conclusions: Preoperative chemotherapy with intravenous 5-fluorouracil negatively affected the mechanisms of liver regeneration after major hepatectomy in rats.

Association between cholesterol and liver regeneration and its significance and potential value in clinical treatment of liver failure / 临床肝胆病杂志

Liver failure is a common severe liver disease syndrome in clinical practice and is one of the critical medical conditions in internal medicine. Massive hepatocyte death is the main pathological feature of liver failure, and its core mechanisms include endotoxin, immune response, and inflammatory cascade reaction. Effective regeneration of hepatocytes to compensate liver function is the physiological basis for promoting the good prognosis of liver failure, which directly affects the prognosis and quality of life of patients with liver failure. It has been found in clinical practice that liver failure patients with a low serum level of cholesterol tend to have an extremely high mortality rate, but as an index of hepatocyte anabolism, the association between cholesterol and hepatocyte regeneration has not been taken seriously. Based on the association between cholesterol and liver regeneration, this article reviews its significance and potential value in the clinical treatment of liver failure, in order to understand the pathogenesis of liver failure from another perspective and provide new ideas for the diagnosis and treatment of liver failure and the development of drugs.

Experimental study on the changes of T1 and T2 values in residual liver of rats after major liver resection and their relationship with liver regeneration process / 中华肝胆外科杂志

Objective:To investigate the changes of T1 and T2 values in residual liver after major liver resection in rats and the relationship with pathologic indices related to liver regeneration.Methods:Seventy healthy male Sprague Dawley rats, SPF grade, aged 7-8 weeks, weighting 250-280 g, were divided into MR scan group ( n=14) and pathologic analysis group ( n=56). The MR scan group was further divided into partial hepatectomy group ( n=7) and the sham operation group ( n=7). MRI T 1 mapping and T 2 mapping were performed before surgery and on day 1, 2, 3, 5, 7, 14, 21 after surgery. T1 and T2 values of liver parenchyma were measured. In the pathologic analysis group, 7 rats were randomly included at each time point before and after surgery for pathologic examination, the diameter and proliferative activity (Ki-67 indices) of hepatocytes were assessed. The changes of imaging and pathologic indices were observed, and the correlations between MR parameters and liver volume and pathologic indices were analyzed. Results:Both T1 and T2 values in liver parenchyma were increased on day 1 after surgery and reached their maximum values on day 2 ( P=0.005 and P<0.001, compared with baseline), then were gradually decreased, and recovered to the preoperative level on day 14 and 21 ( P>0.05), respectively. T2 value was correlated with hepatocyte diameter, liver volume and Ki-67 indices better ( r=0.640, -0.764, 0.765, respectively, all P<0.001). T1 value was correlated with hepatocyte diameter, liver volume and Ki-67 indices ( r=0.472, -0.481 and 0.444, all P<0.001). Conclusion:The T1 and T2 values of rats liver remnant parenchyma showed regular changes, and were correlated with liver regeneration indices, which reflect the microscopic changes of rat liver remnant parenchyma, and are expected to be used for quantitative monitoring of liver remnant regeneration.

The effect of heme oxygenase-1 on liver sinusoidal endothelial cells proliferation and pro-regeneration / 中华肝胆外科杂志

Objective:To investigate the effects of heme oxygenase-1 (HO-1) on hepatic sinusoidal endothelial cells (LSECs) proliferation, migration, and hepatocyte proliferation.Methods:Eighteen male C57BL/6 mouse aged 6-8 weeks old were underwent partial hepatectomy. Cell proliferation and HO-1 expression in residual liver tissue were detected by immunofluorescence histochemistry at 0 d, 2 d and 4 d after operation. In vitro, LSECs were transfected with adenovirus carrying HO-1 gene (HO-1 group), and the cells were transfected with empty vector adenovirus and the non-transfected cells were used as control. In addition, LSECs from different transfection groups were co-cultured with hepatocyte without contact to evaluate the effect of HO-1 expression on promoting hepatocyte proliferation. Western Blotting and RT-PCR were used to detect the protein and mRNA expression of HO-1, inhibitor of DNA binding and or differentiation (Id1), hepatocyte growth factor (HGF) and Wnt2. Cell proliferation was detected by EdU. The ability of cell migration was detected by Transwell migration assay.Results:Compared with 0 d after hepatectomy, LSECs proliferation and HO-1 expression within LSECs were increased significantly at 4 d after surgery. EdU positive rate of LSECs in HO-1 group (27.20±4.80)% was higher than that in empty vector group (12.47±3.30)% and non-transfected group (15.97±2.50)%. The number of LSECs migration in HO-1 group (258.70±36.56) was higher than that in empty vector group (122.00±38.16) and non-transfected group (107.70±30.01). The protein and mRNA expression level of HO-1, Id1, HGF and Wnt2 in HO-1 group were higher than that in empty vector group and non-transfected group. EdU positive rate of hepatocytes that co-cultured with LSECs in HO-1 group (18.33±2.52) % was higher than that in empty vector group (11.33±1.53)% and non-transfected group (11.7±2.08)%. The differences were statistically significant (all P<0.05). Conclusion:Up-regulation of HO-1 promoted LSECs proliferation and migration of, as well as up-regulation of HO-1 in LSECs enhanced the capacity of LSECs to promote hepatocyte proliferation.

Study on the comprehensive effect of splenectomy on liver cirrhosis / 中华肝胆外科杂志

Objective:To study the impact and the mechanism of splenectomy combined with pericardial devascularization on cirrhotic livers.Methods:Serum samples and clinical data were collected preoperatively and postoperatively from 54 patients with cirrhosis who underwent splenectomy combined with pericardial devascularization from May 2013 to Oct 2014 at Beijing You’an Hospital, Capital Medical University. Changes in hepatic arterial and portal venous blood flow, liver function and fibroscan results were analyzed. The levels of nitric oxide (NO), endothelin-1 (ET-1), interleukin-6 (IL-6), hepatocyte growth factor (HGF), transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase 1 (MMP1) were measured.Results:There were 31 males and 23 females, aged(45.48±10.21)years. Free portal vein pressure decreased significantly from (37.0±7.1) cmH 2O (1 cmH 2O=0.098 kPa) to (26.1±5.7) cmH 2O after surgery ( P<0.05). Significant increases in postoperative lumen diameter (4.0±1.0) mm vs (3.1±0.7) mm were observed, accompanied by increase in peak flow velocity and blood flow of the hepatic artery. Significant deductions in lumen diameter (11.9±2.0) mm vs (13.1±1.9) mm, accompanied by reduction of peak flow velocity and blood flow of the portal vein were observed following surgery (all P<0.05). The NO level was significantly elevated immediately after splenectomy and was subsequently remained at high levels. The ET-1 level decreased 2 days after surgery and became fluctuated at low levels. The IL-6 and HGF levels increased significantly 2 days after surgery and decreased gradually after 7 days and 1 month, respectively. The TGF-β1 and the MMP1 levels increased after surgery. The endotoxin level decreased significantly after surgery (all P<0.05). Conclusion:Splenectomy combined with pericardial devascularization induced hepatic blood flow restoration, hepatocyte regeneration and reversal of fibrosis in cirrhotic livers. Splenectomy has a protective effect on cirrhotic liver when combined with pericardial devascularization.

Influencing factors of liver regeneration and their prognostic impact after split liver transplantation / 中华肝胆外科杂志

Objective:To study the influencing factors of liver regeneration and their prognostic impact after split liver transplantation.Methods:The clinical data of 44 patients who underwent split liver transplantation at the Organ Transplant Center of Affiliated Hospital of Qingdao University from January 2015 to July 2021 were analysed. There were 19 males and 25 females, aged (49±12) years old. Based on whether the liver regeneration rate (LRR) was greater than 100%, these patients were divided into the good regeneration group (LRR≥100%, n=24) and the poor regeneration group (LRR<100%, n=20). The differences in the perioperative data and postoperative survival rates between the two groups were compared. The patients were followed up by outpatient reexamination or telephone. Results:On days 15, 30, 90, and 180 after operation, the volume change rates in the transplanted liver were (117.04±7.00)%, (164.03±16.72)%, (180.98±26.30)%, (159.40±26.28)%, respectively. The body mass index, anhepatic period, intraoperative bleeding, intraoperative blood transfusion, hospitalization time, recovery time of liver function, fatty degeneration of donor liver and type of donor liver were the influencing factors of liver regenera-tion after split liver transplantation. The levels of aspartate aminotransferase and alanine aminotransferase on the days 1, 2, 3, 4, 5, 6 and 7 after operation in the group of patient with good regeneration were significantly lower than those in the group of patient with poor regeneration ( P<0.05). The levels of total bilirubin in the group of patient with good regeneration was significantly lower than those in the group of patient with poor regeneration on days 5, 6 and 7 after operation ( P<0.05). The portal vein flow per 100 g of liver mass in the good regeneration group was significantly better than the poor regeneration group on day 1 and 30 after operation. The 6-month cumulative survival rates of the good regeneration group and the poor regeneration group were 95.8% and 70.0% respectively, and the difference was significant ( P=0.017). Conclusions:Body mass index, anhepatic period, intraoperative blood loss, intraoperative blood transfusion, hospitalization time, recovery time of liver function, fatty degeneration of donor liver and type of donor liver were the influencing factors of liver regeneration after split liver transplantation. The prognosis of recipients with poor liver regeneration was significantly worse than recipients with good liver regeneration.

Effects of low-level laser therapy on liver regeneration and laser parameters employed / Efeitos da laserterapia de baixa potência na regeneração hepática e parâmetros empregados de laser

Low-level laser therapy has several biological effects; one of them is tissue regeneration. Recent studies have been held on the application of laser therapy on the liver of rats after partial hepatectomy to promote liver regeneration. The aim of this article was to review the recent studies on the effects of low-level laser therapy on rat liver regeneration after partial hepatectomy and the laser parameters used in those studies. A review of recent relevant literature was performed in Pubmed, Scielo, Medline, and Bireme databases. Articles related to the application of low-level laser therapy on hepatic regeneration were included. Articles with hepatic regeneration in the presence of pathologies were not included. Nine studies were found matching the study criteria. In most studies, low-level laser therapy promoted liver regeneration after partial hepatectomy, without further damage to the remaining liver. Not all laser parameters required for the reproducibility of the study were described by all authors. The therapeutic use of low-level laser therapy in liver regeneration can be promising; however, since the liver is a vital organ, and the laser application is intraoperative, future studies are necessary. The parameters used must be properly described and standardized to allow the reproducibility of the study, in order to define a therapeutic window and thus, consider its clinical use. It is also essential to clarify the mechanisms by which laser promotes liver regeneration to guarantee its safety and therapeutic efficacy.

Laserterapia de baixa potência tem vários efeitos biológicos, sendo um deles a regeneração de tecido. Sua aplicação no fígado de ratos após hepatectomia parcial para promoção de regeneração hepática tem sido estudada recentemente. O objetivo deste artigo foi revisar os estudos recentes dos efeitos da laserterapia de baixa potência na regeneração de fígado de ratos após hepatectomia parcial de fígado e os parâmetros de laser empregados. Uma revisão da literatura relevante recente foi realizada nas bases de dados Pubmed, Scielo, Medline e Bireme. Artigos sobre a aplicação da laserterapia de baixa potência na regeneração de fígado foram incluídos. Artigos sobre regeneração hepática na presença de patologias foram excluídos. Nove estudos foram encontrados correspondendo aos critérios do estudo. Na maioria dos estudos, a laserterapia de baixa potência promoveu regeneração hepática após hepatectomia parcial, sem causar danos adicionais ao fígado remanescente. Não foram descritos todos os parâmetros necessários para reprodutibilidade dos estudos por todos os autores. O uso terapêutico da laserterapia de baixa potência na regeneração de fígado pode ser promissor, entretanto, como o fígado é um órgão vital e a aplicação do laser é intraoperativa, estudos futuros são necessários, assim como os parâmetros da aplicação de laser precisam ser descritos apropriadamente e padronizados, para permitir a reprodutibilidade do estudo, para que uma janela terapêutica possa ser definida e seu uso clínico possa ser considerado. Também é essencial esclarecer através de quais mecanismos o laser promove regeneração de fígado para garantir sua segurança e eficácia terapêutica.

Role of alpha-fetoprotein in prognostic evaluation of patients with liver failure / 临床肝胆病杂志

China is a big country with liver diseases, and various hepatitis viruses, drug poisons, and alcohol can cause liver injury and even liver failure. The key to the prognosis of patients with liver failure is liver self-repair and regeneration. Alpha-fetoprotein (AFP) has been extensively studied as a tumor marker in liver cancer, but its role in liver regeneration in patients with liver failure awaits further studies. This article summarizes the basic research on AFP in liver regeneration and the clinical research on AFP in acute liver failure and acute-on-chronic liver failure (ACLF), as well as the previous research findings of our group that AFP is an important prognostic index and regeneration factor for liver regeneration after hepatitis B virus-related ACLF. The analysis shows that further studies on the role of AFP in the prognosis of various types of liver failure and the mechanism of liver regeneration will help deepen our understanding of AFP and liver regeneration, thereby providing new ideas and methods for the clinical diagnosis, treatment, and prognostic evaluation of patients with various types of liver failure.

Immunotherapy for acute-on-chronic liver failure / 临床肝胆病杂志

Acute-on-chronic liver failure (ACLF) is a life-threatening disease with a high risk of multiple organ failure, sepsis, and death. ACLF activates innate and acquired immune responses in human body and thus leads to the progression of persistent systemic inflammatory response syndrome and multiple organ dysfunction, leading to the high mortality rate of this disease. Dysregulated immune response plays a key role in disease progression, and immunotherapy may help to target immune-mediated organ damage and inhibit the progression of liver failure. This article reviews the role and mechanism of drugs and means with a potential immune regulatory effect in ACLF, in order to provide a reference for immunotherapy for ACLF.