المؤلفون: Qiongwen Zhang, Ting Yu, Huaicheng Tan, Huashan Shi

المصدر: BMC Gastroenterology, Vol 24, Iss 1, Pp 1-13 (2024)

مصطلحات موضوعية: Liver injury, MDSCs, Liver regeneration, Liver fibrosis, Cytokines, Diseases of the digestive system. Gastroenterology, RC799-869

الوصف: Abstract Background The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury. Methods We established four liver injury models of mice including CCl4-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11b+Gr-1+) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-β were measured by ELISA assay and followed by being blocked with specific antibodies. Results The intrahepatic infiltrations of MDSCs with surface marker of CD11b+Gr-1+ remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11b+Ly6G−Ly6Chigh) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-β. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs). Conclusions The dramatically and quickly infiltrated CD11b+Gr-1+ MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1471-230X

URL الوصول: https://doaj.org/article/f773a7a047144dc58c791d7ee715ca65

المؤلفون: Yiyuan Chen, Lijun Meng, Nan Xu, Huan Chen, Xuyong Wei, Di Lu, Shuai Wang, Xiao Xu

المصدر: Cell Communication and Signaling, Vol 22, Iss 1, Pp 1-17 (2024)

مصطلحات موضوعية: Macrophage, Inflammation, Liver regeneration, Tet2, Hepatocellular carcinoma, Medicine, Cytology, QH573-671

الوصف: Abstract Background The remarkable regenerative capacity of the liver enables recovery after radical Hepatocellular carcinoma (HCC) resection. After resection, macrophages secrete interleukin 6 and hepatocyte growth factors to promote liver regeneration. Ten-eleven translocation-2 (Tet2) DNA dioxygenase regulates pro-inflammatory factor secretion in macrophages. In this study, we explored the role of Tet2 in macrophages and its function independent of its enzymatic activity in liver regeneration. Methods The model of liver regeneration after 70% partial hepatectomy (PHx) is a classic universal model for studying reparative processes in the liver. Mice were euthanized at 0, 24, and 48 h after PHx. Enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, immunofluorescence analysis, and flow cytometry were performed to explore immune cell infiltration and liver regenerative capability. Molecular dynamics simulations were performed to study the interaction between Tet2 and signal transducer and activator of transcription 1 (Stat1). Results Tet2 in macrophages negatively regulated liver regeneration in the partial hepatectomy mice model. Tet2 interacted with Stat1, inhibiting the expression of proinflammatory factors and suppressing liver regeneration. The Tet2 inhibitor attenuated the interaction between Stat1 and Tet2, enhanced Stat1 phosphorylation, and promoted hepatocyte proliferation. The proliferative function of the Tet2 inhibitor relied on macrophages and did not affect hepatocytes directly. Conclusion Our findings underscore that Tet2 in macrophages negatively regulates liver regeneration by interacting with Stat1. Targeting Tet2 in macrophages promotes liver regeneration and function after a hepatectomy, presenting a novel target to promote liver regeneration and function. Graphical Abstract Tet2 interacts with Stat1 in the cytoplasm and suppresses IFN-γ-induced macrophage activation. Tet2 inhibitor decreases the combination of Stat1 and Tet2, activating the macrophages through the Jak-Stat pathway. The activation of macrophages increases the transcription and translation of the IL-6 and promotes liver regeneration. Video Abstract

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1478-811X

URL الوصول: https://doaj.org/article/70f8d82fe8ce448b9d293c540cd6b386

المؤلفون: Qian Wang, Zhangtao Long, Fengfeng Zhu, Huajian Li, Zhiqiang Xiang, Hao Liang, Yachen Wu, Xiaoming Dai, Zhu Zhu

المصدر: BMC Genomics, Vol 24, Iss 1, Pp 1-12 (2023)

مصطلحات موضوعية: Liver fibrosis, Liver regeneration, LncRNA, CircRNA, MiRNA, MRNA, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Abstract Background Non-coding RNAs play important roles in liver regeneration; however, their functions and mechanisms of action in the regeneration of fibrotic liver have not been elucidated. We aimed to clarify the expression patterns and regulatory functions of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration. Methods Based on a mouse model of liver fibrosis with 70% hepatectomy, whole-transcriptome profiling was performed using high-throughput sequencing on samples collected at 0, 12, 24, 48, and 72 h after hepatectomy. Hub genes were selected by weighted gene co-expression network analysis and subjected to enrichment analysis. Integrated analysis was performed to reveal the interactions of differentially expressed (DE) lncRNAs, circRNAs, miRNAs, and mRNAs, and to construct lncRNA–mRNA cis- and trans-regulatory networks and lncRNA/circRNA–miRNA–mRNA ceRNA regulatory networks. Real-Time quantitative PCR was used to validate part of the ceRNA network. Results A total of 1,329 lncRNAs, 48 circRNAs, 167 miRNAs, and 6,458 mRNAs were differentially expressed, including 812 hub genes. Based on these DE RNAs, we examined several mechanisms of ncRNA regulatory networks, including lncRNA cis and trans interactions, circRNA parental genes, and ceRNA pathways. We constructed a cis-regulatory core network consisting of 64 lncRNA–mRNA pairs (53 DE lncRNAs and 58 hub genes), a trans-regulatory core network consisting of 103 lncRNA–mRNA pairs (18 DE lncRNAs and 85 hub genes), a lncRNA–miRNA–mRNA ceRNA core regulatory network (20 DE lncRNAs, 12 DE miRNAs, and 33 mRNAs), and a circRNA–miRNA–mRNA ceRNA core regulatory network (5 DE circRNAs, 5 DE miRNAs, and 39 mRNAs). Conclusions These results reveal the expression patterns of lncRNAs, circRNAs, miRNAs, and mRNAs in the proliferative phase of fibrotic liver regeneration, as well as core regulatory networks of mRNAs and non-coding RNAs underlying liver regeneration. The findings provide insights into molecular mechanisms that may be useful in developing new therapeutic approaches to ameliorate diseases that are characterized by liver fibrosis, which would be beneficial for the prevention of liver failure and treatment of liver cancer.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1471-2164

URL الوصول: https://doaj.org/article/2a413b495ed84cc6a181e2b88e4aa12e

المؤلفون: Xi Zhou, Guobin Huang, Lu Wang, Yuanyuan Zhao, Junbo Li, Dong Chen, Lai Wei, Zhishui Chen, Bo Yang

المصدر: Journal of Translational Medicine, Vol 21, Iss 1, Pp 1-14 (2023)

مصطلحات موضوعية: L-carnitine, Lipid metabolism, Liver regeneration, Medicine

الوصف: Abstract Background Lipid metabolism plays an important role in liver regeneration, but its regulation still requires further research. In this study, lipid metabolites involved in mouse liver regeneration at different time points were sequenced and analyzed to study their influence on liver regeneration and its mechanism. Methods Our experiment was divided into two parts. The first part examined lipid metabolites during liver regeneration in mice. In this part, lipid metabolites were sequentially analyzed in the livers of 70% mouse hepatectomy models at 0, 1, 3and 7 days after operation to find the changes of lipid metabolites in the process of liver regeneration. We screened L-carnitine as our research object through metabolite detection. Therefore, in the second part, we analyzed the effects of carnitine on mouse liver regeneration and lipid metabolism during liver regeneration. We divided the mouse into four groups: control group (70% hepatectomy group); L-carnitine group (before operation) (L-carnitine were given before operation); L-carnitine group (after operation)(L-carnitine were given after operation) and L-carnitine + perhexiline maleate (before operation) group. Weighing was performed at 24 h, 36 and 48 h in each group, and oil red staining, HE staining and MPO staining were performed. Tunnel fluorescence staining, Ki67 staining and serological examination. Results Sequencing analysis of lipid metabolites in 70% of mouse livers at different time points after hepatectomy showed significant changes in carnitine metabolites. The results showed that, compared with the control group the mouse in L-carnitine group (before operation) at 3 time points, the number of fat drops in oil red staining was decreased, the number of Ki67 positive cells was increased, the number of MPO positive cells was decreased, the number of Tunnel fluorescence positive cells was decreased, and the liver weight was increased. Serum enzymes were decreased. Compared with control group, L-carnitine group (after operation) showed similar trends in all indexes at 36 and 48 h as L-carnitine group (before operation). L-carnitine + perhexiline maleate (before operation) group compared with control group, the number of fat drops increased, the number of Ki67 positive cells decreased, and the number of MPO positive cells increased at 3 time points. The number of Tunnel fluorescent positive cells increased and serum enzyme increased. However, both liver weights increased. Conclusion L-carnitine can promote liver cell regeneration by promoting lipid metabolism and reduce aseptic inflammation caused by excessive lipid accumulation.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1479-5876

URL الوصول: https://doaj.org/article/8d4ab4dbab7245d6ae4a89a998614715

المؤلفون: Tian Lan, Yang Tai, Chong Zhao, Yang Xiao, Zhu Yang, Linhao Zhang, Can Gan, Wenting Dai, Huan Tong, Chengwei Tang, Zhiyin Huang, Jinhang Gao

المصدر: Inflammation and Regeneration, Vol 43, Iss 1, Pp 1-13 (2023)

مصطلحات موضوعية: Hepatocyte-cholangiocyte transdifferentiation, Cyclooxygenase-2, β-catenin, TGF-β, Chronic liver injury, Liver regeneration, Pathology, RB1-214

الوصف: Abstract Background Hepatocyte-cholangiocyte transdifferentiation (HCT) is a potential origin of proliferating cholangiocytes in liver regeneration after chronic injury. This study aimed to determine HCT after chronic liver injury, verify the impacts of HCT on liver repair, and avoid harmful regeneration by understanding the mechanism. Methods A thioacetamide (TAA)-induced liver injury model was established in wild-type (WT-TAA group) and COX-2 panknockout (KO-TAA group) mice. HCT was identified by costaining of hepatocyte and cholangiocyte markers in vivo and in isolated mouse hepatocytes in vitro. The biliary tract was injected with ink and visualized by whole liver optical clearing. Serum and liver bile acid (BA) concentrations were measured. Either a COX-2 selective inhibitor or a β-catenin pathway inhibitor was administered in vitro. Results Intrahepatic ductular reaction was associated with COX-2 upregulation in chronic liver injury. Immunofluorescence and RNA sequencing indicated that atypical cholangiocytes were characterized by an intermediate genetic phenotype between hepatocytes and cholangiocytes and might be derived from hepatocytes. The structure of the biliary system was impaired, and BA metabolism was dysregulated by HCT, which was mediated by the TGF-β/β-catenin signaling pathway. Genetic deletion or pharmaceutical inhibition of COX-2 significantly reduced HCT in vivo. The COX-2 selective inhibitor etoricoxib suppressed HCT through the TGF-β-TGFBR1-β-catenin pathway in vitro. Conclusions Atypical cholangiocytes can be derived from HCT, which forms a secondary strike by maldevelopment of the bile drainage system and BA homeostasis disequilibrium during chronic liver injury. Inhibition of COX-2 could ameliorate HCT through the COX-2-TGF-β-TGFBR1-β-catenin pathway and improve liver function.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1880-8190

URL الوصول: https://doaj.org/article/8456981888d34eb5ac2a72d53a81c439

المؤلفون: Xin-Hao Hu, Lan Chen, Hao Wu, Yang-Bo Tang, Qiu-Min Zheng, Xu-Yong Wei, Qiang Wei, Qi Huang, Jian Chen, Xiao Xu

المصدر: Stem Cell Research & Therapy, Vol 14, Iss 1, Pp 1-17 (2023)

مصطلحات موضوعية: Cell therapy, Stem cell, End-stage liver disease, Cell transplantation, Liver regeneration, Medicine (General), R5-920, Biochemistry, QD415-436

الوصف: Abstract Liver disease is prevalent worldwide. When it reaches the end stage, mortality rises to 50% or more. Although liver transplantation has emerged as the most efficient treatment for end-stage liver disease, its application has been limited by the scarcity of donor livers. The lack of acceptable donor organs implies that patients are at high risk while waiting for suitable livers. In this scenario, cell therapy has emerged as a promising treatment approach. Most of the time, transplanted cells can replace host hepatocytes and remodel the hepatic microenvironment. For instance, hepatocytes derived from donor livers or stem cells colonize and proliferate in the liver, can replace host hepatocytes, and restore liver function. Other cellular therapy candidates, such as macrophages and mesenchymal stem cells, can remodel the hepatic microenvironment, thereby repairing the damaged liver. In recent years, cell therapy has transitioned from animal research to early human studies. In this review, we will discuss cell therapy in end-stage liver disease treatment, especially focusing on various cell types utilized for cell transplantation, and elucidate the processes involved. Furthermore, we will also summarize the practical obstacles of cell therapy and offer potential solutions.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1757-6512

URL الوصول: https://doaj.org/article/0d2b2ebed7d847f2813279b385276e48

المؤلفون: Gal Reches, Netta R. Blondheim Shraga, Florent Carrette, Assaf Malka, Natalia Saleev, Yehuda Gubbay, Offir Ertracht, Izhak Haviv, Linda M. Bradley, Fred Levine, Ron Piran

المصدر: Inflammation and Regeneration, Vol 42, Iss 1, Pp 1-20 (2022)

مصطلحات موضوعية: Protease-activated receptor-2 (Par2), Hepatitis, Liver regeneration, Concanavalin A, Carbon tetrachloride, Pathology, RB1-214

الوصف: Abstract Background Different factors may lead to hepatitis. Among which are liver inflammation and poisoning. We chose two hepatitis models, typical for these two underlying causes. Thus, we aimed to characterize the role of protease-activated receptor 2 (Par2) in liver regeneration and inflammation to reconcile Par2 conflicting role in many damage models, which sometimes aggravates the induced damage and sometimes alleviates it. Methods WT and knockout (Par2KO) mice were injected with concanavalin A (ConA) to induce immune-mediated hepatitis or with carbon tetrachloride (CCl4) to elicit direct hepatic damage. To distinguish the immune component from the liver regenerative response, we conducted bone marrow (BM) replacements of WT and Par2KO mice and repeated the damage models. Results ConA injection caused limited damage in Par2KO mice livers, while in the WT mice severe damage followed by leukocyte infiltration was evident. Reciprocal BM replacement of WT and Par2KO showed that WT BM-reconstituted Par2KO mice displayed marked liver damage, while in Par2KO BM-reconstituted WT mice, the tissue was generally protected. In the CCl4 direct damage model, hepatocytes regenerated in WT mice, whereas Par2KO mice failed to recover. Reciprocal BM replacement did not show significant differences in hepatic regeneration. In Par2KO mice, hepatitis was more apparent, while WT recovered regardless of the BM origin. Conclusions We conclude that Par2 activation in the immune system aggravates hepatitis and that Par2 activation in the damaged tissue promotes liver regeneration. When we incorporate this finding and revisit the literature reports, we reconciled the conflicts surrounding Par2’s role in injury, recovery, and inflammation.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1880-8190

URL الوصول: https://doaj.org/article/3aba8cd15bd7498c934b490029892569

المؤلفون: Haoqi Chen, Xiaowen Wang, Wenfeng Zhu, Yang Li, Zhenyu Yu, Hua Li, Yang Yang, Shuguang Zhu, Xiaolong Chen, Genshu Wang

المصدر: BMC Surgery, Vol 22, Iss 1, Pp 1-11 (2022)

مصطلحات موضوعية: ALPPS, TACE, FLR, Liver regeneration, Surgery, RD1-811

الوصف: Abstract Objective To evaluate the safety and efficacy of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in the treatment of initially unresectable hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and to preliminarily explore the mechanism of rapid growth of the future liver remnant (FLR). Methods Twenty-four patients with HBV-associated HCC who underwent ALPPS in our hospital from August 2014 to January 2021 were retrospectively studied. Propensity score matching was used to compare oncologic outcomes of patients treated with ALPPS and transarterial chemoembolization (TACE). The expression of YAP and JNK in liver tissue after two stages of ALPPS were detected. Results The median standard liver volume (SLV) was 1471.4 ml. Before second stage of ALPPS, the median FLR increased by 74.4%, and the median FLR/SLV increased from 26.1 to 41.6%. Twenty-two patients (91.7%) received staged hepatectomy after a median interval of 15 (9–24) d. The total incidence of postoperative complications in ALPPS group was 54.5%, and of Clavien–Dindo ≥ IIIb postoperative complications (requiring surgical, endoscopic or radiological intervention under general anesthesia) was 9.1%. There was no significant difference in total complications between ALPPS group and TACE group, but there were lower rate of above grade III complications in the TACE group than that in the ALPPS group. The incidence of complications was lower in laparoscopic-ALPPS than that in open surgery. In ALPPS group, the 1-year, 2-year and 5-year overall survival rate were respectively 71.4%, 33.3% and 4.8%. Interval time was an independent risk factor associated with overall survival rate. There was no significant difference in overall survival rate between ALPPS group and TACE group. For advanced HCC (BCLC stage B and C), ALPPS group was not superior to TACE group in overall survival rate. The expression of YAP and p-JNK in the residual liver tissue after second stage procedure was higher than that after first stage procedure, and the co-expression of YAP and p-JNK was observed in the residual liver tissue. Conclusion ALPPS is a safe and effective treatment for initially unresectable HBV-associated HCC. Laparoscopic technique might improve the effect of ALPPS. YAP and JNK pathway might take a role in rapid FLR increase in ALPPS procedure.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1471-2482

URL الوصول: https://doaj.org/article/415f116982474754a2af1627077caf58

المؤلفون: Caixin Qiu, Shuangshuang Xie, Yajie Sun, Yongquan Yu, Kun Zhang, Xuyang Wang, Jinxia Zhu, Robert Grimm, Wen Shen

المصدر: BMC Gastroenterology, Vol 22, Iss 1, Pp 1-10 (2022)

مصطلحات موضوعية: Magnetic resonance imaging (MRI), Liver regeneration, Hepatectomy, Diffusion kurtosis imaging (DKI), Diseases of the digestive system. Gastroenterology, RC799-869

الوصف: Abstract Background We aimed to evaluate the correlation between the pathological changes and multi-parameter MRI characteristics of liver regeneration (LR) in a standard partial hepatectomy (PH) rat model. Methods Seventy Sprague–Dawley rats were randomly divided into two groups: MR scan group (n = 14) and pathologic analysis (PA) group (n = 56). All 14 rats in the MR group underwent liver T1 mapping, T2 mapping, and diffusion kurtosis imaging before and the 1st, 2nd, 3rd, 5th, 7th, 14th, and 21st day after 70% hepatectomy. Seven rats in the PA group were euthanized at each time point to determine Ki-67 indices, hepatocyte size (HTS), steatosis grade, and inflammation score. Results Liver T1 and T2 values increased to maximum on day 2 (P

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1471-230X

URL الوصول: https://doaj.org/article/aed5423179ed430d9d6fee536a14ac3e

المؤلفون: Yan Zhu, Zhishuai Li, Jixiang Zhang, Mingqi Liu, Xiaoqing Jiang, Bin Li

المصدر: BMC Genomics, Vol 23, Iss 1, Pp 1-11 (2022)

مصطلحات موضوعية: Portal vein occlusion, Liver regeneration, lncRNA, Transcriptome, WGCNA, Biotechnology, TP248.13-248.65, Genetics, QH426-470

الوصف: Abstract Background Portal vein ligation (PVL)-induced liver hypertrophy increases future liver remnant (FLR) volume and improves resectability of large hepatic carcinoma. However, the molecular mechanism by which PVL facilitates liver hypertrophy remains poorly understood. Methods To gain mechanistic insight, we established a rat PVL model and carried out a comprehensive transcriptome analyses of hepatic lobes preserving portal blood supply at 0, 1, 7, and 14-day after PVL. The differentially expressed (DE) long-non coding RNAs (lncRNAs) and mRNAs were applied to conduct weighted gene co-expression network analysis (WGCNA). LncRNA-mRNA co-expression network was constructed in the most significant module. The modules and genes associated with PVL-induced liver hypertrophy were assessed through quantitative real-time PCR. Results A total of 4213 DElncRNAs and 6809 DEmRNAs probesets, identified by transcriptome analyses, were used to carry out WGCNA, by which 10 modules were generated. The largest and most significant module (marked in black_M6) was selected for further analysis. Gene Ontology (GO) analysis of the module exhibited several key biological processes associated with liver regeneration such as complement activation, IL-6 production, Wnt signaling pathway, autophagy, etc. Sixteen mRNAs (Notch1, Grb2, IL-4, Cops4, Stxbp1, Khdrbs2, Hdac2, Gnb3, Gng10, Tlr2, Sod1, Gosr2, Rbbp5, Map3k3, Golga2, and Rev3l) and ten lncRNAs (BC092620, AB190508, EF076772, BC088302, BC158675, BC100646, BC089934, L20987, BC091187, and M23890) were identified as hub genes in accordance with gene significance value, module membership value, protein–protein interaction (PPI) and lncRNA-mRNA co-expression network. Furthermore, the overexpression of 3 mRNAs (Notch1, Grb2 and IL-4) and 4 lncRNAs (BC089934, EF076772, BC092620, and BC088302) was validated in hypertrophic liver lobe tissues from PVL rats and patients undergoing hepatectomy after portal vein embolization (PVE). Conclusions Microarray and WGCNA analysis revealed that the 3 mRNAs (Notch1, Grb2 and IL-4) and the 4 lncRNAs (BC089934, EF076772, BC092620 and BC088302) may be promising targets for accelerating liver regeneration before extensive hepatectomy.

وصف الملف: electronic resource

Relation: https://doaj.org/toc/1471-2164

URL الوصول: https://doaj.org/article/baae179101514190a128337619f0e121