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1
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Yen CC, Yen CS, Tsai HW, Yeh MM, Hong TM, Wang WL, Liu IT, Shan YS, Yen CJ. Second harmonic generation microscopy reveals the spatial orientation of glutamine-potentiated liver regeneration after hepatectomy. Hepatol Commun 2025; 9:e0640. [PMID: 40048459 PMCID: PMC11888978 DOI: 10.1097/hc9.0000000000000640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/30/2024] [Indexed: 03/10/2025] Open
Abstract
BACKGROUND Glutamine (Gln) is a critical amino acid for energy expenditure. It participates in extracellular matrix (ECM) formation and circulates in the hepatic parenchyma in a spatial-oriented manner. Posthepatectomy liver mass recovery poses a regenerative challenge. However, little is known about the role of Gln in liver regeneration, notably the spatial orientation in the remodeling process. This study aimed to elucidate Gln-potentiated liver regeneration and ECM remodeling after mass loss. METHODS We studied the regenerative process in hepatectomized mice supplemented with Gln. Second harmonic generation/two-photon excitation fluorescence microscopy, an artificial intelligence-assisted structure-based imaging, was used to demonstrate the spatial-oriented process in a hepatic acinus. RESULTS Gln promotes liver mass regrowth through the cell cycle, Gln metabolism, and adipogenesis pathways after hepatectomy. Ornithine transaminase, one of the upregulated enzymes, showed temporal, spatial, and functional correspondence with the regeneration process. Second harmonic generation/two-photon excitation fluorescence microscopy highlighted transient hepatic steatosis and ECM collagen synthesis, predominantly in the portal tract instead of the central vein area. Structural remodeling was also observed in the portal tract area. CONCLUSIONS Gln promotes liver regeneration through cellular proliferation and metabolic reprogramming after hepatectomy. Using structure-based imaging, we found that Gln potentiated hepatic steatosis and ECM collagen deposition predominantly in the portal tract area. These results highlighted the spatial orientation and mechanistic implications of Gln in liver regeneration.
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Affiliation(s)
- Chih-Chieh Yen
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Sheng Yen
- Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Nursing, Meiho University, Pingtung, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Matthew M. Yeh
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington, USA
- Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Tse-Ming Hong
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Lung Wang
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - I-Ting Liu
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yan-Shen Shan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Li X, Feng J, Cheng H, Jin N, Jin S, Liu Z, Xu J, Xie J. Human umbilical cord mesenchymal stem cells enhance liver regeneration and decrease collagen content in fibrosis mice after partial hepatectomy by activating Wnt/β-catenin signaling. Acta Biochim Biophys Sin (Shanghai) 2024. [PMID: 39716885 DOI: 10.3724/abbs.2024207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2024] Open
Abstract
Liver fibrosis is a critical stage in the progression of various chronic liver diseases to cirrhosis and liver cancer. Early inhibition of liver fibrosis is crucial for the treatment of liver disease. Hepatectomy, a common treatment for liver-related diseases, promotes liver regeneration. However, in the context of liver fibrosis, liver regeneration is hindered. Many studies have shown that mesenchymal stem cells (MSCs) can promote liver regeneration after partial hepatectomy (PH). However, there are few reports on the impact of MSC therapy on liver regeneration post-PH in the context of hepatic fibrosis. The objective of this study is to examine the impact of MSCs on liver regeneration following PH in the fibrotic liver and uncover the related molecular mechanisms. This study reveals that MSC therapy significantly enhances liver function and mitigates liver inflammation after PH in the context of hepatic fibrosis. MSCs also significantly promote liver regeneration and alleviate liver fibrosis. In addition, this study identifies the role of MSCs in promoting liver regeneration and alleviating liver fibrosis via the activation of Wnt/β-catenin signaling. The combination of MSCs with hepatectomy may offer a novel approach for the treatment of liver fibrotic diseases.
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Affiliation(s)
- Xuewei Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jinghui Feng
- Academy of Medical Sciences, Shanxi Medical University, Taiyuan 030001, China
| | - Haiqin Cheng
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Ning Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Shanshan Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xu
- Department of Hepatobiliary and Pancreatic Surgery and Liver Transplant Center, the First Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan 030001, China
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3
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Zhang S, Yu M, Wang F, Li S, Li X, Hu H, Zhang Z, Zhu X, Tian W. Salidroside promotes liver regeneration after partial hepatectomy in mice by modulating NLRP3 inflammasome-mediated pyroptosis pathway. Biochem Biophys Res Commun 2024; 735:150678. [PMID: 39270555 DOI: 10.1016/j.bbrc.2024.150678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 07/26/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024]
Abstract
Insufficient residual liver tissue after partial hepatectomy (PH) may lead to serious complications such as hepatic failure and small-for-size syndrome. Salidroside (SAL) is obtained from Rhodiola rosea through modernized separation and extraction and has been validated for treating various liver diseases. It's yet unknown, nevertheless, how SAL affects liver regeneration after PH. This study aimed to determine whether SAL could promote liver regeneration after PH in mice. We demonstrated that SAL could attenuate liver injury after PH and promote hepatocyte proliferation and liver mass recovery. Mechanistically, SAL inhibited the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, attenuating pyroptosis. RNA-seq analysis indicated that SAL downregulated the transcription of NLRP3 and GSDMD genes and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the NOD-like receptor signaling pathway was significantly enriched in down-regulated signaling pathways. Notably, SAL in combination with the NLRP3 inhibitor MCC950 did not further inhibit NLRP3 inflammasome and promote liver mass recovery. In summary, our findings proved that SAL could be a potential agent for improving liver function and promoting liver regeneration after PH.
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Affiliation(s)
- Saiya Zhang
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Meilu Yu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Fen Wang
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Sha Li
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Xuefei Li
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Hongyu Hu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Zhen Zhang
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Xiangpeng Zhu
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China
| | - Weiqian Tian
- Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China.
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Kayalı A, Bora ES, Acar H, Erbaş O. Evaluation of the Reparative Effect of Sinomenine in an Acetaminophen-Induced Liver Injury Model. Curr Issues Mol Biol 2024; 46:923-933. [PMID: 38275673 PMCID: PMC10814253 DOI: 10.3390/cimb46010059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/09/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
Due to its rising global prevalence, liver failure treatments are urgently needed. Sinomenine (SIN), an alkaloid from sinomenium acutum, is being studied for its liver-repair properties due to Acetaminophen (APAP) overdose. SIN's effect on APAP-induced hepatotoxicity in rats was examined histologically and biochemically. Three groups of 30 adult male Wistar rats were created: control, APAP-only, and APAP + SIN. Histopathological and biochemical analyses were performed on liver samples after euthanasia. SIN is significantly protected against APAP damage. Compared to APAP-only, SIN reduced cellular injury and preserved hepatocellular architecture. The APAP + SIN Group had significantly lower ALT, MDA, and GSH levels, protecting against hepatocellular damage and oxidative stress. SIN also had dose-dependent antioxidant properties. When examining critical regulatory proteins, SIN partially restored Sirtuin 1 (SIRT1) levels. While BMP-7 levels were unaffected, histopathological evidence and hepatocyte damage percentages supported SIN's liver-restorative effect. SIN protected and repaired rats' livers from APAP-induced liver injury. This study suggests that SIN may treat acute liver damage, warranting further research into its long-term effects, optimal dosage, and clinical applications. These findings aid liver-related emergency department interventions and life-saving treatments.
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Affiliation(s)
- Ahmet Kayalı
- Department of Emergency Medicine, Faculty of Medicine, Izmir Katip Çelebi University, Izmir 35270, Turkey; (A.K.); (H.A.)
| | - Ejder Saylav Bora
- Department of Emergency Medicine, Izmir Atatürk Research and Training Hospital, Izmir 35360, Turkey
| | - Hüseyin Acar
- Department of Emergency Medicine, Faculty of Medicine, Izmir Katip Çelebi University, Izmir 35270, Turkey; (A.K.); (H.A.)
| | - Oytun Erbaş
- Department of Physiology, Faculty of Medicine, Demiroğlu Bilim University, Istanbul 34395, Turkey;
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Dauchy RT, Sauer LA, Blask DE. Dietary Linoleic Acid: An Omega-6 Fatty Acid Essential for Liver Regeneration in Buffalo Rats. Comp Med 2023; 73:295-311. [PMID: 37652672 PMCID: PMC10702281 DOI: 10.30802/aalas-cm-23-000004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 05/02/2023] [Accepted: 05/04/2023] [Indexed: 09/02/2023]
Abstract
Rodents are currently the most common animals used for hepatic surgical resection studies that investigate liver regeneration, chronic liver disease, acute liver failure, hepatic metastasis, hepatic function, and hepatic cancer. Our previous work has shown that dietary consumption of linoleic acid (LA) stimulates the growth of rodent and human tumors in vivo. Here we compared 3 diets - a 5% corn oil diet (control), a diet deficient in essential fatty acids (EFAD), and an EFAD supplemented with LA in amounts equal to those in the control diet (EFAD+LA). We hypothesized that consumption of the LA provided in the EFAD+LA diet would elevate plasma levels of LA and stimulate regeneration in rats after a 70% hepatectomy (HPX), and that regeneration would not occur in the EFAD rats. Each diet group was comprised of 30 male and 30 female Buffalo rats (BUFF/CrCrl). Rats were fed one of the 3 diets and water ad libitum. After 8 wk on the assigned diet, rats were underwent a 70% HPX. On days 4 and 21 after HPX, 30 male and 30 female rats from each diet group were anesthetized for in vivo study and then were euthanized for tissue collection. For the in vivo study, arterial and venous blood samples were collected from the liver. LA-, glucose-, and O₂ -uptake, and lactate- and CO₂ -output were significantly higher in LA-replete rats as compared with LA-deficient rats. After a 70% HPX, the remaining liver mass in control and EFAD+LA groups had doubled at day 4, reaching 60% of the original total weight, and had regenerated completely at day 21. However, no regeneration occurred in the EFAD group. At day 4 the portions of livers removed from the control and EFAD+LA groups had significantly higher content of LA, protein, cAMP, and DNA as compared with their livers on day 21. [³ H]thymidine incorporation into liver DNA was significantly higher in the 2 LA-replete groups, with male values greater than female values, as compared with LA-deficient group. These data indicate that liver regeneration after HPX is dependent on dietary LA. Understanding the mechanisms of LA-dependent liver regeneration in rats supports our current efforts to enhance successful surgical resection therapies in humans.
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Key Words
- akt, serine-threonine protein kinase
- a-v, arterial-venous
- ce, cholesterol esters
- cl, caudate lobe
- cp, caudate process
- icl, inferior caudate lobe
- irll, inferior right lateral lobe
- ivc, inferior vena cava
- efad, essential fatty acid deficient
- egfr, epithelial growth factor receptor
- erk1/2, extracellular signal regulated kinase p44/46 (mapk, mitogen-activated protein kinase)
- fa, fatty acid
- ffar, free fatty acid receptor
- ffa, free fatty acids
- g protein, guanine nucleotide binding protein
- hpx, 70% partial hepatectomy
- la, linoleic acid
- lll, left lateral lobe
- lml, left median lobe
- ml, middle or median lobe
- rll, right lateral lobe
- rml, right median lobe
- scl, superior caudate lobe
- srll, superior right lateral lobe
- pi3k, phosphatidylinositol-3-kinase/akt
- pl, phospholipids
- tfa, total fatty acids
- tgl, triglycerides
- wnt/β-catenin, wingless and int-1/β catenin
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Affiliation(s)
- Robert T Dauchy
- Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane, Louisiana
| | | | - David E Blask
- Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane, Louisiana
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6
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Luque LM, Carlevaro CM, Llamoza Torres CJ, Lomba E. Physics-based tissue simulator to model multicellular systems: A study of liver regeneration and hepatocellular carcinoma recurrence. PLoS Comput Biol 2023; 19:e1010920. [PMID: 36877741 PMCID: PMC10019748 DOI: 10.1371/journal.pcbi.1010920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/16/2023] [Accepted: 02/03/2023] [Indexed: 03/07/2023] Open
Abstract
We present a multiagent-based model that captures the interactions between different types of cells with their microenvironment, and enables the analysis of the emergent global behavior during tissue regeneration and tumor development. Using this model, we are able to reproduce the temporal dynamics of regular healthy cells and cancer cells, as well as the evolution of their three-dimensional spatial distributions. By tuning the system with the characteristics of the individual patients, our model reproduces a variety of spatial patterns of tissue regeneration and tumor growth, resembling those found in clinical imaging or biopsies. In order to calibrate and validate our model we study the process of liver regeneration after surgical hepatectomy in different degrees. In the clinical context, our model is able to predict the recurrence of a hepatocellular carcinoma after a 70% partial hepatectomy. The outcomes of our simulations are in agreement with experimental and clinical observations. By fitting the model parameters to specific patient factors, it might well become a useful platform for hypotheses testing in treatments protocols.
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Affiliation(s)
- Luciana Melina Luque
- Instituto de Física de Líquidos y Sistemas Biológicos - CONICET. La Plata, Argentina
- * E-mail: (LML); (CMC)
| | - Carlos Manuel Carlevaro
- Instituto de Física de Líquidos y Sistemas Biológicos - CONICET. La Plata, Argentina
- Departamento de Ingeniería Mecánica, Universidad Tecnológica Nacional, Facultad Regional La Plata, La Plata, Argentina
- * E-mail: (LML); (CMC)
| | | | - Enrique Lomba
- Instituto de Química Física Rocasolano - CSIC. Madrid, España
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7
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Delgado-Coello B, Navarro-Alvarez N, Mas-Oliva J. The Influence of Interdisciplinary Work towards Advancing Knowledge on Human Liver Physiology. Cells 2022; 11:cells11223696. [PMID: 36429123 PMCID: PMC9688355 DOI: 10.3390/cells11223696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/11/2022] [Accepted: 11/13/2022] [Indexed: 11/23/2022] Open
Abstract
The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary approaches searching to improve liver regeneration and, therefore, human health. Here, we provide a brief history of the milestones that have advanced liver surgery, and review some of the new insights offered by the interdisciplinary work using animals, in vitro models, tissue engineering, or mathematical models to help advance the knowledge on liver regeneration. We also present several of the main approaches currently available aiming at providing liver support and overcoming organ shortage and we conclude with some of the challenges found in clinical practice and the ethical issues that have concomitantly emerged with the use of those approaches.
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Affiliation(s)
- Blanca Delgado-Coello
- Department of Structural Biology and Biochemistry, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
- Correspondence:
| | - Nalu Navarro-Alvarez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
- Departament of Molecular Biology, Universidad Panamericana School of Medicine, Mexico City 03920, Mexico
- Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA
| | - Jaime Mas-Oliva
- Department of Structural Biology and Biochemistry, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
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Huang W, Han N, Du L, Wang M, Chen L, Tang H. A narrative review of liver regeneration-from models to molecular basis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1705. [PMID: 34988214 PMCID: PMC8667151 DOI: 10.21037/atm-21-5234] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/04/2021] [Indexed: 12/11/2022]
Abstract
Objective To elucidate the characteristics of different liver regeneration animal models, understand the activation signals and mechanisms related to liver regeneration, and obtain a more comprehensive conception of the entire liver regeneration process. Background Liver regeneration is one of the most enigmatic and fascinating phenomena of the human organism. Despite suffering significant injuries, the liver still can continue to perform its complex functions through the regeneration system. Although advanced topics on liver regeneration have been proposed; unfortunately, complete regeneration of the liver has not been achieved until now. Therefore, increasing understanding of the liver regenerative process can help improve our treatment of liver failure. It will provide a new sight for the treatment of patients with liver injury in the clinic. Methods Literatures on liver regeneration animal models and involved basic research on molecular mechanisms were retrieved to analyze the characteristics of different models and those related to molecular basis. Conclusions The process of liver regeneration is complex and intricate, consisting of various and interactive pathways. There is sufficient evidence to demonstrate that liver regeneration is similar between humans and rodents. At the same time, many of the same cytokines, growth factors, and signaling pathways are relevant. There are many gaps in our current knowledge. Understanding of this knowledge will provide more supportive clinical treatment strategies, including small-scale liver transplantation and high-quality regenerative process after surgical resection, and offer possible targets to treat the dysregulation of regeneration that occurs in chronic hepatic diseases and tumors. Current research work, such as the use of animal models as in vivo vectors for high-quality human hepatocytes, represents a unique and significant cutting edge in the field of liver regeneration.
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Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ning Han
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Liyu Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China.,Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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Chen Y, Xu Z, Zeng Y, Liu J, Wang X, Kang Y. Altered metabolism by autophagy defection affect liver regeneration. PLoS One 2021; 16:e0250578. [PMID: 33914811 PMCID: PMC8084245 DOI: 10.1371/journal.pone.0250578] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 04/08/2021] [Indexed: 11/19/2022] Open
Abstract
Autophagy is the primary intracellular catabolic process for degrading and recycling long-lived proteins and damaged organelles, which maintains cellular homeostasis. Autophagy has key roles in development and differentiation. By using the mouse with liver specific knockout of autophagy related gene 5 (Atg5), a gene essential for autophagy, we investigated the possible role of autophagy in liver regeneration after 70% partial hepatectomy (PHx). Ablation of autophagy significantly impaired mouse liver regeneration, and this impairment was associated with reduced hepatocellular proliferation rate, down-regulated expression of cyclins and tumor suppressors, and increased hepatocellular apoptosis via the intrinsic apoptotic pathway. Ablation of autophagy does not affect IL-6 and TNF-α response after PHx, but the altered hepatic and systemic metabolic responses were observed in these mice, including reduced ATP and hepatic free fatty acid levels in the liver tissue, increased glucose level in the serum. Autophagy is required to promote hepatocellular proliferation by maintaining normal hepatic and systemic metabolism and suppress hepatocellular apoptosis in liver regeneration.
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Affiliation(s)
- Yi Chen
- Clinical Research Service Center, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Zhiwei Xu
- Clinical Research Service Center, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Yanli Zeng
- Department of Infectious Diseases, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Junping Liu
- Department of Infectious Diseases, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Xuemei Wang
- Department of Traditional Chinese Medicine, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
| | - Yi Kang
- Department of Infectious Diseases, Henan Provincia People’s Hospital, Zhengzhou University People’s Hospital, Henan Province, Zhengzhou, China
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10
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Cerium Oxide Nanoparticles: A New Therapeutic Tool in Liver Diseases. Antioxidants (Basel) 2021; 10:antiox10050660. [PMID: 33923136 PMCID: PMC8146351 DOI: 10.3390/antiox10050660] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 12/15/2022] Open
Abstract
Oxidative stress induced by the overproduction of free radicals or reactive oxygen species (ROS) has been considered as a key pathogenic mechanism contributing to the initiation and progression of injury in liver diseases. Consequently, during the last few years antioxidant substances, such as superoxide dismutase (SOD), resveratrol, colchicine, eugenol, and vitamins E and C have received increasing interest as potential therapeutic agents in chronic liver diseases. These substances have demonstrated their efficacy in equilibrating hepatic ROS metabolism and thereby improving liver functionality. However, many of these agents have not successfully passed the scrutiny of clinical trials for the prevention and treatment of various diseases, mainly due to their unspecificity and consequent uncontrolled side effects, since a minimal level of ROS is needed for normal functioning. Recently, cerium oxide nanoparticles (CeO2NPs) have emerged as a new powerful antioxidant agent with therapeutic properties in experimental liver disease. CeO2NPs have been reported to act as a ROS and reactive nitrogen species (RNS) scavenger and to have multi-enzyme mimetic activity, including SOD activity (deprotionation of superoxide anion into oxygen and hydrogen peroxide), catalase activity (conversion of hydrogen peroxide into oxygen and water), and peroxidase activity (reducing hydrogen peroxide into hydroxyl radicals). Consequently, the beneficial effects of CeO2NPs treatment have been reported in many different medical fields other than hepatology, including neurology, ophthalmology, cardiology, and oncology. Unlike other antioxidants, CeO2NPs are only active at pathogenic levels of ROS, being inert and innocuous in healthy cells. In the current article, we review the potential of CeO2NPs in several experimental models of liver disease and their safety as a therapeutic agent in humans as well.
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11
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Plaza-Díaz J, Álvarez-Mercado AI, Robles-Sánchez C, Navarro-Oliveros M, Morón-Calvente V, Toribio-Castelló S, Sáez-Lara MJ, MacKenzie A, Fontana L, Abadía-Molina F. NAIP expression increases in a rat model of liver mass restoration. J Mol Histol 2021; 52:113-123. [PMID: 33237375 DOI: 10.1007/s10735-020-09928-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/13/2020] [Indexed: 11/26/2022]
Abstract
The neuronal apoptosis inhibitory protein (NAIP) is a constituent of the NLRC4 inflammasome, which plays a key role in innate immunity, and an antiapoptotic protein. Recently, we reported the previously undescribed role of NAIP in cell division. The liver is one of the body's most actively regenerative organs. Given the novel mitotic role of NAIP, we examined its expression in hepatic mass restoration. The major liver lobe of Wistar rats was removed, and samples from both newly formed liver tissue, assessed by positive Ki67 immunostaining, and the remnant, intact liver lobes from hepatectomized rats were taken 3 and 7 days after surgery. Naip5 and Naip6 mRNA levels were significantly higher in regenerating hepatic tissue than in intact liver lobe tissue, and this increase was also observed at the protein level. Naip5 and Naip6 mRNA in situ hybridization showed that this increase occurred in the hepatic parenchyma. The histology of the regenerated liver tissue was normal, with the exception of a noticeable deficiency of hepatic lobule central veins. The results of this study suggest the involvement of NAIP in liver mass restoration following partial hepatectomy.
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Affiliation(s)
- Julio Plaza-Díaz
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071, Granada, Spain
- Institute of Nutrition and Food Technology "José Mataix", Biomedical Research Center, Avda. del Conocimiento S/N, Armilla, 18016, Granada, Spain
- Instituto de Investigación Biosanitaria Ibs.GRANADA, Avda. de Madrid 15, 18012, Granada, Spain
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, K1H 8L1, Canada
| | - Ana I Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071, Granada, Spain
- Institute of Nutrition and Food Technology "José Mataix", Biomedical Research Center, Avda. del Conocimiento S/N, Armilla, 18016, Granada, Spain
- Instituto de Investigación Biosanitaria Ibs.GRANADA, Avda. de Madrid 15, 18012, Granada, Spain
| | - Cándido Robles-Sánchez
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071, Granada, Spain
- Institute of Nutrition and Food Technology "José Mataix", Biomedical Research Center, Avda. del Conocimiento S/N, Armilla, 18016, Granada, Spain
| | - Miguel Navarro-Oliveros
- Instituto de Investigación Biosanitaria Ibs.GRANADA, Avda. de Madrid 15, 18012, Granada, Spain
| | - Virginia Morón-Calvente
- Department of Diabetes. Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Sofía Toribio-Castelló
- IBSAL, IBMCC, University of Salamanca-CSIC, Cancer Research Center, 37007, Salamanca, Spain
| | - María José Sáez-Lara
- Institute of Nutrition and Food Technology "José Mataix", Biomedical Research Center, Avda. del Conocimiento S/N, Armilla, 18016, Granada, Spain
- Instituto de Investigación Biosanitaria Ibs.GRANADA, Avda. de Madrid 15, 18012, Granada, Spain
- Department of Biochemistry and Molecular Biology I, School of Sciences, University of Granada, 18071, Granada, Spain
| | - Alex MacKenzie
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, K1H 8L1, Canada
- Department of Pediatrics, University of Ottawa, Ottawa, ON, K1H 8L1, Canada
| | - Luis Fontana
- Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, 18071, Granada, Spain
- Institute of Nutrition and Food Technology "José Mataix", Biomedical Research Center, Avda. del Conocimiento S/N, Armilla, 18016, Granada, Spain
- Instituto de Investigación Biosanitaria Ibs.GRANADA, Avda. de Madrid 15, 18012, Granada, Spain
| | - Francisco Abadía-Molina
- Institute of Nutrition and Food Technology "José Mataix", Biomedical Research Center, Avda. del Conocimiento S/N, Armilla, 18016, Granada, Spain.
- Department of Cell Biology, School of Sciences, University of Granada, 18071, Granada, Spain.
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Xu F, Hua C, Tautenhahn HM, Dirsch O, Dahmen U. The Role of Autophagy for the Regeneration of the Aging Liver. Int J Mol Sci 2020; 21:ijms21103606. [PMID: 32443776 PMCID: PMC7279469 DOI: 10.3390/ijms21103606] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023] Open
Abstract
Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk.
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Affiliation(s)
- Fengming Xu
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Chuanfeng Hua
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Hans-Michael Tautenhahn
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Olaf Dirsch
- Institute of Pathology, Klinikum Chemnitz gGmbH, 09111 Chemnitz, Germany;
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
- Correspondence: ; Tel.: +49-03641-9325350
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Kojima H, Nakamura K, Kupiec-Weglinski JW. Therapeutic targets for liver regeneration after acute severe injury: a preclinical overview. Expert Opin Ther Targets 2020; 24:13-24. [PMID: 31906729 DOI: 10.1080/14728222.2020.1712361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Liver transplantation is the only viable treatment with a proven survival benefit for acute liver failure (ALF). Donor organ shortage is, however, a major hurdle; hence, alternative approaches that enable liver regeneration and target acute severe hepatocellular damage are necessary.Areas covered: This article sheds light on therapeutic targets for liver regeneration and considers their therapeutic potential. ALF following extensive hepatocyte damage and small-for-size syndrome (SFSS) are illuminated for the reader while the molecular mechanisms of liver regeneration are assessed in accordance with relevant therapeutic strategies. Furthermore, liver background parameters and predictive biomarkers that might associate with liver regeneration are reviewed.Expert opinion: There are established and novel experimental strategies for liver regeneration to prevent ALF resulting from SFSS. Granulocyte-colony stimulating factor (G-CSF) is a promising agent targeting liver regeneration after acute severe injury. Autophagy and hepatocyte senescence represent attractive new targets for liver regeneration in acute severe hepatic injury. Liver support strategies, including tissue engineering, constitute novel regenerative means; the success of this is dependent on stem cell research advances. However, there is no firm clinical evidence that these supportive strategies may alleviate hepatocellular damage until liver transplantation becomes available or successful self-liver regeneration occurs.
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Affiliation(s)
- Hidenobu Kojima
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Kojiro Nakamura
- Department of Surgery, Kyoto University, Kyoto, Japan.,Department of Surgery, Nishi-Kobe Medical Center, Kobe, Japan
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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O’Keefe K, DeSantis K, Altrieth A, Nelson D, Taroc E, Stabell A, Pham M, Larsen M. Regional Differences following Partial Salivary Gland Resection. J Dent Res 2020; 99:79-88. [PMID: 31765574 PMCID: PMC6927217 DOI: 10.1177/0022034519889026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Regenerative medicine aims to repair, replace, or restore function to tissues damaged by aging, disease, or injury. Partial organ resection is not only a common clinical approach in cancer therapy but also an experimental injury model used to examine mechanisms of regeneration and repair in organs. We performed a partial resection, or partial sialoadenectomy, in the female murine submandibular salivary gland (SMG) to establish a model for investigation of repair mechanisms in salivary glands (SGs). After partial sialoadenectomy, we performed whole-gland measurements over a period of 56 d and found that the gland increased slightly in size. We used microarray analysis and immunohistochemistry (IHC) to examine messenger RNA and protein changes in glands over time. Microarray analysis identified dynamic changes in the transcriptome 3 d after injury that were largely resolved by day 14. At the 3-d time point, we detected gene signatures for cell cycle regulation, inflammatory/repair response, and extracellular matrix (ECM) remodeling in the partially resected glands. Using quantitative IHC, we identified a transient proliferative response throughout the gland. Both secretory epithelial and stromal cells expressed Ki67 that was detectable at day 3 and largely resolved by day 14. IHC also revealed that while most of the gland underwent a wound-healing response that resolved by day 14, a small region of the gland showed an aberrant sustained fibrotic response characterized by increased levels of ECM deposition, sustained Ki67 levels in stromal cells, and a persistent M2 macrophage response through day 56. The partial submandibular salivary gland resection model provides an opportunity to examine a normal healing response and an aberrant fibrotic response within the same gland to uncover mechanisms that prevent wound healing and regeneration in mammals. Understanding regional differences in the wound-healing responses may ultimately affect regenerative therapies for patients.
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Affiliation(s)
- K.J. O’Keefe
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, State University of New York, University at Albany, Albany, NY, USA
- Department of Biological Sciences, State University of New York, University at Albany, Albany, NY, USA
| | - K.A. DeSantis
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, State University of New York, University at Albany, Albany, NY, USA
- Gen*NY*Sis Center for Excellence in Cancer, Department of Environmental Health Sciences, School of Public Health, State University of New York, University at Albany, Albany, NY, USA
| | - A.L. Altrieth
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, State University of New York, University at Albany, Albany, NY, USA
- Department of Biological Sciences, State University of New York, University at Albany, Albany, NY, USA
| | - D.A. Nelson
- Department of Biological Sciences, State University of New York, University at Albany, Albany, NY, USA
| | - E.Z.M. Taroc
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, State University of New York, University at Albany, Albany, NY, USA
- Department of Biological Sciences, State University of New York, University at Albany, Albany, NY, USA
| | - A.R. Stabell
- Department of Biological Sciences, State University of New York, University at Albany, Albany, NY, USA
- Current address: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA
| | - M.T. Pham
- Department of Biological Sciences, State University of New York, University at Albany, Albany, NY, USA
- Current address: The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Midlothian, Scotland, UK
| | - M. Larsen
- Molecular, Cellular, Developmental, and Neural Biology Graduate Program, State University of New York, University at Albany, Albany, NY, USA
- Department of Biological Sciences, State University of New York, University at Albany, Albany, NY, USA
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15
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Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2019; 100:62-73. [PMID: 31669133 DOI: 10.1016/j.semcdb.2019.10.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Liver regeneration is an important and necessary process that the liver depends on for recovery from injury. The regeneration process consists of a complex network of cells and organs, including liver cells (parenchymal and non-parenchymal cells) and extrahepatic organs (thyroid, adrenal glands, pancreas, duodenum, spleen, and autonomic nervous system). The regeneration process of a normal, healthy liver depends mainly on hepatocyte proliferation, growth, and programmed cell death. Cell proliferation and growth are regulated in a cooperative manner by interleukin (IL)-6/janus kinase (Jak)/signal transducers and activators of transcription-3 (STAT3), and phosphoinositide 3-kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathways. The IL-6/Jak/STAT3 pathway regulates hepatocyte proliferation and protects against cell death and oxidative stress. The PI3-K/PDK1/Akt pathway is primarily responsible for the regulation of cell size, sending mitotic signals in addition to pro-survival, antiapoptotic and antioxidative signals. Though programmed cell death may interfere with liver regeneration in a pathological situation, it seems to play an important role during the termination phase, even in a normal, healthy liver regeneration. However, further study is needed to fully elucidate the mechanisms regulating the processes of liver regeneration with regard to cell-to-cell and organ-to-organ networks at the molecular and cellular levels.
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Affiliation(s)
- Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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16
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Wei X, Luo L, Chen J. Roles of mTOR Signaling in Tissue Regeneration. Cells 2019; 8:cells8091075. [PMID: 31547370 PMCID: PMC6769890 DOI: 10.3390/cells8091075] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/06/2019] [Accepted: 09/07/2019] [Indexed: 12/11/2022] Open
Abstract
The mammalian target of rapamycin (mTOR), is a serine/threonine protein kinase and belongs to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family. mTOR interacts with other subunits to form two distinct complexes, mTORC1 and mTORC2. mTORC1 coordinates cell growth and metabolism in response to environmental input, including growth factors, amino acid, energy and stress. mTORC2 mainly controls cell survival and migration through phosphorylating glucocorticoid-regulated kinase (SGK), protein kinase B (Akt), and protein kinase C (PKC) kinase families. The dysregulation of mTOR is involved in human diseases including cancer, cardiovascular diseases, neurodegenerative diseases, and epilepsy. Tissue damage caused by trauma, diseases or aging disrupt the tissue functions. Tissue regeneration after injuries is of significance for recovering the tissue homeostasis and functions. Mammals have very limited regenerative capacity in multiple tissues and organs, such as the heart and central nervous system (CNS). Thereby, understanding the mechanisms underlying tissue regeneration is crucial for tissue repair and regenerative medicine. mTOR is activated in multiple tissue injuries. In this review, we summarize the roles of mTOR signaling in tissue regeneration such as neurons, muscles, the liver and the intestine.
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Affiliation(s)
- Xiangyong Wei
- Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China.
| | - Lingfei Luo
- Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China.
| | - Jinzi Chen
- Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Beibei, Chongqing 400715, China.
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17
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Associations of Oxidative Stress and Postoperative Outcome in Liver Surgery with an Outlook to Future Potential Therapeutic Options. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:3950818. [PMID: 30906502 PMCID: PMC6393879 DOI: 10.1155/2019/3950818] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 01/02/2019] [Indexed: 12/16/2022]
Abstract
Several types of surgical procedures have shown to elicit an inflammatory stress response, leading to substantial cytokine production and formation of oxygen-based or nitrogen-based free radicals. Chronic liver diseases including cancers are almost always characterized by increased oxidative stress, in which hepatic surgery is likely to potentiate at least in the short term and hereby furthermore impair the hepatic redox state. During liver resection, intermittent inflow occlusion is commonly applied to prevent excessive blood loss but resulting ischemia and reperfusion of the liver have been linked to increased oxidative stress, leading to impairment of cell functions and subsequent cell death. In the field of liver transplantation, ischemia/reperfusion injury has extensively been investigated in the last decades and has recently been in the scientific focus again due to increased use of marginal donor organs and new machine perfusion concepts. Therefore, given the intriguing role of oxidative stress in the pathogenesis of numerous diseases and in the perioperative setting, the interest for a therapeutic antioxidative agent has been present for several years. This review is aimed at giving an introduction to oxidative stress in surgical procedures in general and then examines the role of oxidative stress in liver surgery in particular, discussing both transplantation and resection. Results from studies in the animal and human settings are included. Finally, potential therapeutic agents that might be beneficial in reducing the burden of oxidative stress in hepatic diseases and during surgery are presented. While there is compelling evidence from animal models and a limited number of clinical studies showing that oxidative stress plays a major role in both liver resection and transplantation and several recent studies have suggested a potential for antioxidative treatment in chronic liver disease (e.g., steatosis), the search for effective antioxidants in the field of liver surgery is still ongoing.
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18
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Impact of Three-Dimentional Culture Systems on Hepatic Differentiation of Puripotent Stem Cells and Beyond. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018. [PMID: 30357683 DOI: 10.1007/978-981-13-0947-2_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Generation of functional hepatocytes from human pluripotent stem cells (hPSCs) is a vital tool to produce large amounts of human hepatocytes, which hold a great promise for biomedical and regenerative medicine applications. Despite a tremendous progress in developing the differentiation protocols recapitulating the developmental signalling and stages, these resulting hepatocytes from hPSCs yet achieve maturation and functionality comparable to those primary hepatocytes. The absence of 3D milieu in the culture and differentiation of these hepatocytes may account for this, at least partly, thus developing an optimal 3D culture could be a step forward to achieve this aim. Hence, review focuses on current development of 3D culture systems for hepatic differentiation and maturation and the future perspectives of its application.
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Cook D, Achanta S, Hoek JB, Ogunnaike BA, Vadigepalli R. Cellular network modeling and single cell gene expression analysis reveals novel hepatic stellate cell phenotypes controlling liver regeneration dynamics. BMC SYSTEMS BIOLOGY 2018; 12:86. [PMID: 30285726 PMCID: PMC6171157 DOI: 10.1186/s12918-018-0605-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 08/21/2018] [Indexed: 12/26/2022]
Abstract
Background Recent results from single cell gene and protein regulation studies are starting to uncover the previously underappreciated fact that individual cells within a population exhibit high variability in the expression of mRNA and proteins (i.e., molecular variability). By combining cellular network modeling, and high-throughput gene expression measurements in single cells, we seek to reconcile the high molecular variability in single cells with the relatively low variability in tissue-scale gene and protein expression and the highly coordinated functional responses of tissues to physiological challenges. In this study, we focus on relating the dynamic changes in distributions of hepatic stellate cell (HSC) functional phenotypes to the tightly regulated physiological response of liver regeneration. Results We develop a mathematical model describing contributions of HSC functional phenotype populations to liver regeneration and test model predictions through isolation and transcriptional characterization of single HSCs. We identify and characterize four HSC transcriptional states contributing to liver regeneration, two of which are described for the first time in this work. We show that HSC state populations change in vivo in response to acute challenges (in this case, 70% partial hepatectomy) and chronic challenges (chronic ethanol consumption). Our results indicate that HSCs influence the dynamics of liver regeneration through steady-state tissue preconditioning prior to an acute insult and through dynamic control of cell state balances. Furthermore, our modeling approach provides a framework to understand how balances among cell states influence tissue dynamics. Conclusions Taken together, our combined modeling and experimental studies reveal novel HSC transcriptional states and indicate that baseline differences in HSC phenotypes as well as a dynamic balance of transitions between these phenotypes control liver regeneration responses. Electronic supplementary material The online version of this article (10.1186/s12918-018-0605-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Daniel Cook
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA.,Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Sirisha Achanta
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jan B Hoek
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Babatunde A Ogunnaike
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA
| | - Rajanikanth Vadigepalli
- Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, DE, USA. .,Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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Haga S, Yimin, Ozaki M. Relevance of FXR-p62/SQSTM1 pathway for survival and protection of mouse hepatocytes and liver, especially with steatosis. BMC Gastroenterol 2017; 17:9. [PMID: 28086800 PMCID: PMC5237313 DOI: 10.1186/s12876-016-0568-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 12/27/2016] [Indexed: 01/12/2023] Open
Abstract
Background Liver injury and regeneration involve complicated processes and are affected by various physio-pathological conditions. Surgically, severe liver injury after surgical resection often leads to fatal liver failure, especially with some underlying pathological conditions such as steatosis. Therefore, protection from the injury of hepatocytes and liver is a serious concern in various clinical settings. Methods We studied the effects of the farnesoid X receptor (FXR) on cell survival and steatosis in mouse hepatocytes (AML12 mouse liver cells) and investigated their molecular mechanisms. We next studied whether or not FXR improves liver injury, regeneration and steatosis in a mouse model of partial hepatectomy (PH) with steatosis. Results An FXR-specific agonist, GW4064, induced expressions of the p62/SQSTM1 gene and protein in AML12 mouse liver cells. Because we previously reported p62/SQSTM1 as a key molecule for antioxidation and cell survival in hepatocytes, we next examined the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) and induction of the antioxidant molecules by GW4064. GW4064 activated Nrf2 and subsequently induced antioxidant molecules (Nrf2, catalase, HO-1, and thioredoxin). We also examined expressions of pro-survival and cell protective molecules associated with p62/SQSTM1. Expectedly, GW4064 induced phosphorylation of Akt, expression of the anti-apoptotic
molecules (Bcl-xL and Bcl-2), and reduced harmful hepatic molecules (Fas ligand and Fas). GW4064 promoted
hepatocyte survival, which was cancelled by p62/SQSTM1 siRNA. These findings suggest the potential relevance of the FXR-p62/SQSTM1 pathway for the survival and protection of hepatocytes. Furthermore, GW4064 induced the expression of small heterodimer partners (SHP) and suppressed liver X receptor (LXR)-induced steatosis in hepatocytes, expecting the in vivo protective effect of FXR on liver injury especially with steatosis. In the hepatectomy model of db/db mice with fatty liver, pre-treatment by GW4064 significantly reduced post-PH liver injury (serum levels of LDH, AST & ALT and histological study) and improved steatosis. The key molecules, p62/SQSTM1, Nrf2 and SHP were upregulated in fatty liver tissue by GW4064 treatment. Conclusions The present study is the first to demonstrate the relevance of FXR-p62/SQSTM1 and -SHP in the protection against injury of hepatocytes and post-PH liver, especially with steatosis. Electronic supplementary material The online version of this article (doi:10.1186/s12876-016-0568-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sanae Haga
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N-12, W-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan
| | - Yimin
- Department of Advanced Medicine, Graduate School of Medicine, Hokkaido University, N-15, W-7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N-12, W-5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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Morales-González Á, Bautista M, Madrigal-Santillán E, Posadas-Mondragón A, Anguiano-Robledo L, Madrigal-Bujaidar E, Álvarez-González I, Fregoso-Aguilar T, Gayosso-Islas E, Sánchez-Moreno C, Morales-González JA. Nrf2 modulates cell proliferation and antioxidants defenses during liver regeneration induced by partial hepatectomy. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:7801-7811. [PMID: 31966628 DOI: pmid/31966628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 05/21/2017] [Indexed: 02/07/2023]
Abstract
The objective was to determine the regulatory dynamic of Nrf2 during liver regeneration and the administration of EtOH and/or the G. schiedeanum extract. Male Wistar rats weighing 200-230 g were subjected to a 70% partial hepatectomy; they were then divided into three groups (groups 1-3). During the experiment, animals in Group 1 drank only water. The other two groups (2-3) received an intragastric dose of ethanol (1.5 g/kg BW, solution at 40% in isotonic saline solution). Additionally, rats in group 3 received a geranium extract daily at a dose of 300 mg/kg BW i.g. EtOh and/or Geranium schiedeanum was administered to rats with regenerating livers for 7 days. At the end of treatment, the activity was determined of the antioxidant enzymes, DNA concentration, TBARS, and TAC, in addition to the expression of Nrf-2, Cyclin D1, and Nqo1. EtOH increased ROS and Nrf-2, which activated the antioxidant defenses and delayed liver proliferation. On the other hand, Geranium schiedeanum exerted an antioxidant effect, diminishing ROS, but Nrf-2 expression increased, favoring liver proliferation through the increase of DNA concentration and the overexpression of Cyclin D1, however it did not activate the antioxidant defenses. In sum, it can be concluded that Nrf-2 possesses a regulatory dynamic that is evident in the presence of a toxic agent (EtOH) and/or a phytochemical agent with antioxidant capacity (Geranium schiedeanum) during liver regeneration.
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Affiliation(s)
- Ángel Morales-González
- Escuela Superior de Cómputo, Instituto Politécnico Nacional México
- Área Académica de Farmacia, ICSa, Universidad Autónoma del Estado de Hidalgo México
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional México
- Laboratorio de Farmacología Molecular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional México
- Laboratorio de Genética, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional México
- Depto. de Fisiología, Laboratorio de Hormonas y Conducta, ENCB campus Zacatenco, Instituto Politécnico Nacional México
- Área Académica de Enfermería, ICSa, Universidad Autónoma del Estado de Hidalgo México
| | - Mirandeli Bautista
- Área Académica de Farmacia, ICSa, Universidad Autónoma del Estado de Hidalgo México
| | - Eduardo Madrigal-Santillán
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional México
| | - Araceli Posadas-Mondragón
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional México
| | - Liliana Anguiano-Robledo
- Laboratorio de Farmacología Molecular, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional México
| | - Eduardo Madrigal-Bujaidar
- Laboratorio de Genética, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional México
| | - Isela Álvarez-González
- Laboratorio de Genética, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional México
| | - Tomás Fregoso-Aguilar
- Depto. de Fisiología, Laboratorio de Hormonas y Conducta, ENCB campus Zacatenco, Instituto Politécnico Nacional México
| | - Evila Gayosso-Islas
- Área Académica de Enfermería, ICSa, Universidad Autónoma del Estado de Hidalgo México
| | | | - José A Morales-González
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional México
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Lu Y, Liu P, Fu P, Chen Y, Nan D, Yang X. Comparison of the DWI and Gd-EOB-DTPA-enhanced MRI on assessing the hepatic ischemia and reperfusion injury after partial hepatectomy. Biomed Pharmacother 2016; 86:118-126. [PMID: 27951418 DOI: 10.1016/j.biopha.2016.11.123] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 11/09/2016] [Accepted: 11/27/2016] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE To compare two different imaging media, diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) and Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) with perfusion parameters Ktrans, Kep, and relative contrast enhancement index (RCEI), in assessing the liver function via ischemia/perfusion injury (IRI) + partial hepatectomy rat model. METHODS Rats underwent 0, 30 and 60min of ischemia/reperfusion with 30% of hepatectomy before subjected to Gd-EOB-DTPA-enhanced MRI in addition to 99mTc-GSA scintigraphy. For 99mTc-GSA scintigraphy test, the receptor index LHL15, modified receptor index and the blood clearance index HH15 were recorded. Apparent diffusion coefficient (ADC) was evaluated by using both mono- and bi-exponential models, and perfusion parameters Ktrans, Kep, and RCEI were measured. Liver function is tested by measuring activity of serum ALT, AST and PT. Histological analysis was performed by H&E and Ki-67 staining. RESULTS 99mTc-GSA dynamic imaging analysis demonstrated that LHL15 was increased and HH15 was decreased as the extension of ischemia/reperfusion time. ADC value estimated by MRI was significantly increased (P<0.05) in 30min IRI group compared with 0min and 60min IRI groups, respectively. Ktrans value was gradually and significantly decreased (P<0.05) as the extension of IRI time, but there was no significant difference (P>0.05) in Kep value between at 30min and 60min IRI, and RCEI value was significantly higher (P<0.05) in 30min IR compared with 0min and 60min IRI group. Serum level of ALT, AST and PT were gradually and significantly (P<0.05) increased as the extension of IRI time. Histological analysis showed that there was a remarkable difference between 30min and 60min IRI, as protein expression of Ki-67 was significantly higher (P<0.05) in 30min IRI group. CONCLUSION Fast ADC bi-exponential model in DWI and RCEI in Gd-EOB-DTPA-enhanced MRI showed the good correlation in assessment of liver function after partial hepatectomy, showing consistency with our histological findings. The Ktrans in Gd-EOB-DTPA-enhanced MRI could be a potent parameter for assessing the early ischemic injury, but not the severity of the hepatic injury, in accordance with the correlation with our biochemical findings.
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Affiliation(s)
- Yu Lu
- Department of Nuclear Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Pengfei Liu
- Department of Radiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Peng Fu
- Department of Nuclear Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yaodong Chen
- Department of Abdomen Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Dong Nan
- Department of Radiology, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xiuhua Yang
- Department of Abdomen Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
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Meier M, Andersen KJ, Knudsen AR, Nyengaard JR, Hamilton-Dutoit S, Mortensen FV. Liver regeneration is dependent on the extent of hepatectomy. J Surg Res 2016; 205:76-84. [PMID: 27621002 DOI: 10.1016/j.jss.2016.06.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 05/18/2016] [Accepted: 06/07/2016] [Indexed: 12/25/2022]
Abstract
BACKGROUND The upper limit for the size of hepatectomy is approximately 90% in rats. The aim of the study was to assess quantitatively using stereological methods the impact on liver function, regeneration rate (RR), and hepatocyte proliferation of varying hepatectomy size in a rat model. MATERIALS AND METHODS A total of 104 male Wistar rats were subjected to 30%, 70%, or 90% partial hepatectomy, sham operation, or no operation. Euthanization and harvesting of liver tissue and blood took place at postoperative days 1, 3, and 5 (n = 8 per group). Liver-specific biochemistry and RR were evaluated. Hepatocyte proliferation was estimated by immunohistochemical staining for Ki-67 antigen using unbiased stereological principles. RESULTS Liver RR in the 90% group increased by a 6.6 fold during the 5 postoperative days compared with only a minor increase in both the 70% and 30% partial hepatectomy groups. The highest number of Ki-67-positive hepatocytes was observed in the 70% group at postoperative day 1 and for the 90% group at postoperative day 3. Prothrombin-proconvertin ratio was significantly lower in the 90% group 1 d after surgery compared with all other groups, however, nearly normalized at postoperative day 5. CONCLUSIONS We show that liver RR and the number of proliferating hepatocytes increase, whereas the initial hepatic synthetic capacity decreases with increasing hepatectomy size.
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Affiliation(s)
- Michelle Meier
- Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | | | | | - Jens Randel Nyengaard
- Stereology & Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus, Denmark
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Pok S, Barn VA, Wong HJ, Blackburn AC, Board P, Farrell GC, Teoh NC. Testosterone regulation of cyclin E kinase: A key factor in determining gender differences in hepatocarcinogenesis. J Gastroenterol Hepatol 2016; 31:1210-9. [PMID: 26574916 DOI: 10.1111/jgh.13232] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 10/27/2015] [Accepted: 10/28/2015] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM While gender differences in hepatocellular carcinoma (HCC) are profound, the mechanism is unclear. Using castration and hormone replacement strategies, we tested whether these gender differences are attributable to testosterone or estradiol/progesterone effects on cell cycle regulators and p53. METHODS We studied dysplastic liver and HCCs in intact and castrated diethylnitrosamine-injected C57BL/6J male and female mice, with or without hormonal replacement. Effects of sex steroids on proliferation and survival of primary hepatocytes and primary HCC cells were also characterized. RESULTS Diethylnitrosamine-injected female mice displayed fewer dysplastic foci and slower onset of HCC than male mice, with smaller/more differentiated tumors and fewer metastases. Castration of diethylnitrosamine-injected male mice reduced cyclin E kinase and augmented hepatocyte apoptosis compared with intact male mice; estradiol/progesterone enhanced these effects. In intact female mice, cyclin E kinase activity was less than in males; testosterone administered to ovariectomized female mice upregulated cyclin E, increased cyclin E kinase, and accelerated hepatocarcinogenesis. In vitro, testosterone increased expression of cell cycle regulators (cyclin D1, cyclin E, and cyclin-dependent kinase 2) and reduced p53 and p21, which enhanced hepatocyte viability. In contrast, estradiol both suppressed hepatocyte cell cycle markers, upregulated p53 and reduced viability of hepatocytes and HCC cells. CONCLUSIONS Testosterone is the positive regulator of hepatocyte cell cycle via cyclin E, while estradiol plays a negative role by effects of p53 and p21. Together, both sex hormones determine the male predominance of gender differences in hepatocarcinogenesis.
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Affiliation(s)
- Sharon Pok
- Liver Research Group, Australian National University Medical School, Canberra Hospital
| | - Vanessa A Barn
- Liver Research Group, Australian National University Medical School, Canberra Hospital
| | - Heng Jian Wong
- Liver Research Group, Australian National University Medical School, Canberra Hospital
| | - Anneke C Blackburn
- Molecular Genetics Group, John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia
| | - Philip Board
- Molecular Genetics Group, John Curtin School of Medical Research, Canberra, Australian Capital Territory, Australia
| | - Geoffrey C Farrell
- Liver Research Group, Australian National University Medical School, Canberra Hospital
| | - Narci C Teoh
- Liver Research Group, Australian National University Medical School, Canberra Hospital
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Porada CD, Atala AJ, Almeida-Porada G. The hematopoietic system in the context of regenerative medicine. Methods 2015; 99:44-61. [PMID: 26319943 DOI: 10.1016/j.ymeth.2015.08.015] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 07/06/2015] [Accepted: 08/23/2015] [Indexed: 12/16/2022] Open
Abstract
Hematopoietic stem cells (HSC) represent the prototype stem cell within the body. Since their discovery, HSC have been the focus of intensive research, and have proven invaluable clinically to restore hematopoiesis following inadvertent radiation exposure and following radio/chemotherapy to eliminate hematologic tumors. While they were originally discovered in the bone marrow, HSC can also be isolated from umbilical cord blood and can be "mobilized" peripheral blood, making them readily available in relatively large quantities. While their ability to repopulate the entire hematopoietic system would already guarantee HSC a valuable place in regenerative medicine, the finding that hematopoietic chimerism can induce immunological tolerance to solid organs and correct autoimmune diseases has dramatically broadened their clinical utility. The demonstration that these cells, through a variety of mechanisms, can also promote repair/regeneration of non-hematopoietic tissues as diverse as liver, heart, and brain has further increased their clinical value. The goal of this review is to provide the reader with a brief glimpse into the remarkable potential HSC possess, and to highlight their tremendous value as therapeutics in regenerative medicine.
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Affiliation(s)
- Christopher D Porada
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, United States.
| | - Anthony J Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, United States.
| | - Graça Almeida-Porada
- Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, United States.
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Mesenchymal Stromal Cell-Derived Factors Promote Tissue Repair in a Small-for-Size Ischemic Liver Model but Do Not Protect against Early Effects of Ischemia and Reperfusion Injury. J Immunol Res 2015; 2015:202975. [PMID: 26380314 PMCID: PMC4561317 DOI: 10.1155/2015/202975] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Accepted: 05/27/2015] [Indexed: 12/21/2022] Open
Abstract
Loss of liver mass and ischemia/reperfusion injury (IRI) are major contributors to postresectional liver failure and small-for-size syndrome. Mesenchymal stromal cell- (MSC-) secreted factors are described to stimulate regeneration after partial hepatectomy. This study investigates if liver-derived MSC-secreted factors also promote liver regeneration after resection in the presence of IRI.
C57BL/6 mice underwent IRI of 70% of their liver mass, alone or combined with 50% partial hepatectomy (PH). Mice were treated with MSC-conditioned medium (MSC-CM) or unconditioned medium (UM) and sacrificed after 6 or 24 hours (IRI group) or after 48 hours (IRI + PH group). Blood and liver tissue were analyzed for tissue injury, hepatocyte proliferation, and gene expression. In the IRI alone model, serum ALT and AST levels, hepatic tissue damage, and inflammatory cytokine gene expression showed no significant differences between both treatment groups. In the IRI + PH model, significant reduction in hepatic tissue damage as well as a significant increase in hepatocyte proliferation was observed after MSC-CM treatment. Conclusion. Mesenchymal stromal cell-derived factors promote tissue regeneration of small-for-size livers exposed to ischemic conditions but do not protect against early ischemia and reperfusion injury itself. MSC-derived factors therefore represent a promising treatment strategy for small-for-size syndrome and postresectional liver failure.
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Madrigal-Santillán E, Bautista M, Gayosso-De-Lucio JA, Reyes-Rosales Y, Posadas-Mondragón A, Morales-González &A, Soriano-Ursúa MA, García-Machorro J, Madrigal-Bujaidar E, Álvarez-González I, Morales-González JA. Hepatoprotective effect of Geranium schiedeanum against ethanol toxicity during liver regeneration. World J Gastroenterol 2015; 21:7718-7729. [PMID: 26167072 PMCID: PMC4491959 DOI: 10.3748/wjg.v21.i25.7718] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 02/25/2015] [Accepted: 04/09/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the effect of an extract of Geranium schiedeanum (Gs) as a hepatoprotective agent against ethanol (EtOH)-induced toxicity in rats.
METHODS: Male Wistar rats weighing 200-230 g were subjected to a 70% partial hepatectomy (PH); they were then divided into three groups (groups 1-3). During the experiment, animals in group 1 drank only water. The other two groups (2-3) drank an aqueous solution of EtOH (40%, v/v). Additionally, rats in group 3 received a Gs extract daily at a dose of 300 mg/kg body weight intragastically. Subsequently, to identify markers of liver damage in serum, alanine aminotransferase, aspartate aminotransferase, albumin and bilirubin were measured by colorimetric methods. Glucose, triglyceride and cholesterol concentrations were also determined. In addition, oxidative damage was estimated by measuring lipid peroxidation [using thiobarbituric-acid reactive substances (TBARS)] in both plasma and the liver and by measuring the total concentration of antioxidants in serum and the total antioxidant capacity in the liver. In addition, a liver mass gain assessment, total DNA analysis and a morpho-histological analysis of the liver from animals in all three groups were performed and compared. Finally, the number of deaths observed in the three groups was analyzed.
RESULTS: Administration of the Geranium shiedeanum extract significantly reduced the unfavorable effect of ethanol on liver regeneration (restitution liver mass: PH-EtOH group 60.68% vs PH-Gs-EtOH group 69.22%). This finding was congruent with the reduced levels of hepatic enzymes and the sustained or increased levels of albumin and decreased bilirubin in serum. The extract also modified the metabolic processes that regulate glucose and lipid levels, as observed from the serum measurements. Lower antioxidant levels and the liver damage induced by EtOH administration appeared to be mitigated by the extract, as observed from the TBARs (PH-EtOH group 200.14 mmol/mg vs PH-Gs-EtOH group 54.20 mmol/mg; P < 0.05), total status of antioxidants (PH-EtOH group 1.43 mmol/L vs PH-Gs-EtOH group 1.99 mmol/L; P < 0.05), total antioxidant capacity values, liver mass gain and total DNA determination (PH-EtOH group 4.80 mg/g vs PH-Gs-EtOH 9.10 mg/g; P < 0.05). Overall, these processes could be related to decreased mortality in these treated animals.
CONCLUSION: The administered extract showed a hepatoprotective effect, limiting the EtOH-induced hepatotoxic effects. This effect can be related to modulating oxido-reduction processes.
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Best J, Manka P, Syn WK, Dollé L, van Grunsven LA, Canbay A. Role of liver progenitors in liver regeneration. Hepatobiliary Surg Nutr 2015; 4:48-58. [PMID: 25713804 DOI: 10.3978/j.issn.2304-3881.2015.01.16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 01/20/2015] [Indexed: 12/16/2022]
Abstract
During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.
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Affiliation(s)
- Jan Best
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Paul Manka
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Wing-Kin Syn
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Laurent Dollé
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Leo A van Grunsven
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Ali Canbay
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
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Haga S, Ozawa T, Yamada Y, Morita N, Nagashima I, Inoue H, Inaba Y, Noda N, Abe R, Umezawa K, Ozaki M. p62/SQSTM1 plays a protective role in oxidative injury of steatotic liver in a mouse hepatectomy model. Antioxid Redox Signal 2014; 21:2515-30. [PMID: 24925527 PMCID: PMC4245881 DOI: 10.1089/ars.2013.5391] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
AIMS Liver injury and regeneration involve complicated processes and are affected by various physio-pathological factors. We investigated the mechanisms of steatosis-associated liver injury and delayed regeneration in a mouse model of partial hepatectomy. RESULTS Initial regeneration of the steatotic liver was significantly delayed after hepatectomy. Although hepatocyte proliferation was not significantly suppressed, severe liver injury with oxidative stress (OS) occurred immediately after hepatectomy in the steatotic liver. Fas-ligand (FasL)/Fas expression was upregulated in the steatotic liver, whereas the expression of antioxidant and anti-apoptotic molecules (catalase/MnSOD/Ref-1 and Bcl-2/Bcl-xL/FLIP, respectively) and p62/SQSTM1, a steatosis-associated protein, was downregulated. Interestingly, pro-survival Akt was not activated in response to hepatectomy, although it was sufficiently expressed even before hepatectomy. Suppression of p62/SQSTM1 increased FasL/Fas expression and reduced nuclear factor erythroid 2-related factor-2 (Nrf-2)-dependent antioxidant response elements activity and antioxidant responses in steatotic and nonsteatotic hepatocytes. Exogenously added FasL induced severe cellular OS and necrosis/apoptosis in steatotic hepatocytes, with only the necrosis being inhibited by pretreatment with antioxidants, suggesting that FasL/Fas-induced OS mainly leads to necrosis. Furthermore, p62/SQSTM1 re-expression in the steatotic liver markedly reduced liver injury and improved liver regeneration. INNOVATION This study is the first which demonstrates that reduced expression of p62/SQSTM1 plays a crucial role in posthepatectomy acute injury and delayed regeneration of steatotic liver, mainly via redox-dependent mechanisms. CONCLUSION In the steatotic liver, reduced expression of p62/SQSTM1 induced FasL/Fas overexpression and suppressed antioxidant genes, mainly through Nrf-2 inactivation, which, along with the hypo-responsiveness of Akt, caused posthepatectomy necrotic/apoptotic liver injury and delayed regeneration, both mainly via a redox-dependent mechanism.
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Affiliation(s)
- Sanae Haga
- 1 Laboratory of Molecular and Functional Bio-imaging, Faculty of Health Sciences, Hokkaido University , Sapporo, Japan
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Yahya WNW, Kadri NA, Ibrahim F. Cell patterning for liver tissue engineering via dielectrophoretic mechanisms. SENSORS 2014; 14:11714-34. [PMID: 24991941 PMCID: PMC4168452 DOI: 10.3390/s140711714] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 06/20/2014] [Accepted: 06/25/2014] [Indexed: 12/27/2022]
Abstract
Liver transplantation is the most common treatment for patients with end-stage liver failure. However, liver transplantation is greatly limited by a shortage of donors. Liver tissue engineering may offer an alternative by providing an implantable engineered liver. Currently, diverse types of engineering approaches for in vitro liver cell culture are available, including scaffold-based methods, microfluidic platforms, and micropatterning techniques. Active cell patterning via dielectrophoretic (DEP) force showed some advantages over other methods, including high speed, ease of handling, high precision and being label-free. This article summarizes liver function and regenerative mechanisms for better understanding in developing engineered liver. We then review recent advances in liver tissue engineering techniques and focus on DEP-based cell patterning, including microelectrode design and patterning configuration.
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Affiliation(s)
- Wan Nurlina Wan Yahya
- Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Nahrizul Adib Kadri
- Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
| | - Fatimah Ibrahim
- Department of Biomedical Engineering, Faculty of Engineering, University of Malaya, Kuala Lumpur 50603, Malaysia.
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Toderke EL, Baretta GAP, Gama Filho OP, Matias JEF. Sirolimus influence on hepatectomy-induced liver regeneration in rats. Rev Col Bras Cir 2014; 41:203-7. [DOI: 10.1590/s0100-69912014000300012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Accepted: 07/25/2013] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE: To evaluate the influence of sirolimus on liver regeneration triggered by resection of 70% of the liver of adult rats. METHODS: we used 40 Wistar rats randomly divided into two groups (study and control), each group was divided into two equal subgroups according to the day of death (24 hours and seven days). Sirolimus was administered at a dose of 1mg/kg in the study group and the control group was given 1 ml of saline. The solutions were administered daily since three days before hepatectomy till the rats death to removal of the regenerated liver, conducted in 24 hours or 7 days after hepatectomy. Liver regeneration was measured by the KWON formula, by thenumber of mitotic figures (hematoxylin-eosin staining) and by the immunohistochemical markers PCNA and Ki-67. RESULTS: there was a statistically significant difference between the 24h and the 7d groups. When comparing the study and control groups in the same period, there was a statistically significant variation only for Ki-67, in which there were increased numbers of hepatocytes in cell multiplication in the 7d study group compared with the 7d control group (p = 0.04). CONCLUSION: there was no negative influence of sirolimus in liver regeneration and there was a positive partial effect at immunohistochemistry with Ki-67.
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Periwal V, Gaillard JR, Needleman L, Doria C. Mathematical model of liver regeneration in human live donors. J Cell Physiol 2014; 229:599-606. [PMID: 24446196 DOI: 10.1002/jcp.24482] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 09/30/2013] [Indexed: 01/31/2023]
Abstract
Liver regeneration after injury occurs in many mammals. Rat liver regenerates after partial hepatectomy over a period of 2 weeks while human liver regeneration takes several months. Notwithstanding this enormous difference in time-scales, with new data from five human live liver transplant donors, we show that a mathematical model of rat liver regeneration can be transferred to human, with all biochemical interactions and signaling unchanged. Only six phenomenological parameters need change, and three of these parameter changes are rescalings of rate constants by the ratio of human lifespan to rat lifespan. Data from three donor subjects with approximately equal resections were used to fit the three parameters and the data from the other two donor subjects was used to independently verify the fit.
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Affiliation(s)
- V Periwal
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Castillo-Mora RC, Aranda-Anzaldo A. Reorganization of the DNA-nuclear matrix interactions in a 210 kb genomic region centered on c-myc after DNA replication in vivo. J Cell Biochem 2012; 113:2451-63. [PMID: 22396210 DOI: 10.1002/jcb.24123] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In the interphase nucleus of metazoan cells DNA is organized in supercoiled loops anchored to a nuclear matrix (NM). DNA loops are operationally classified in structural and facultative. Varied evidence indicates that DNA replication occurs in replication foci organized upon the NM and that structural DNA loops may correspond to the replicons in vivo. In normal rat liver the hepatocytes are arrested in G0 but synchronously re-enter the cell cycle after partial-hepatectomy leading to liver regeneration. Using this model we have previously determined that the DNA loops corresponding to a gene-rich genomic region move in a sequential fashion towards the NM during replication and then return to their original configuration in newly quiescent cells, once liver regeneration has been achieved. In the present work we determined the organization into structural DNA loops of a gene-poor region centered on c-myc and tracked-down its movement at the peak of S phase and after the return to cellular quiescence during and after liver regeneration. The results confirmed that looped DNA moves towards the NM during replication but in this case the configuration of the gene-poor region into DNA loops becomes reorganized and after replication only the loop containing c-myc resembles the original in the control G0 hepatocytes. Our results suggest that the local chromatin configuration around potentially active genes constraints the formation of specific structural DNA loops after DNA replication, while in non-coding regions the structural DNA loops are only loosely determined after DNA replication by structural constraints that modulate the DNA-NM interactions.
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Affiliation(s)
- Rebeca C Castillo-Mora
- Facultad de Medicina, Universidad Autónoma del Estado de México, Paseo Tollocan y Jesús Carranza s/n, Toluca, Edo. México, Mexico
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Jin LM, Jin SF, Liu YX, Zhou L, Xie HY, Yan S, Xu X, Zheng SS. Ischemic preconditioning enhances hepatocyte proliferation in the early phase after ischemia under hemi-hepatectomy in rats. Hepatobiliary Pancreat Dis Int 2012; 11:521-6. [PMID: 23060398 DOI: 10.1016/s1499-3872(12)60217-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Ischemia/reperfusion (I/R) injury is an important barrier to liver surgery and transplantation because it impairs remnant liver/reduced-size-graft regeneration. Ischemic preconditioning (IPC), as an effective measure to overcome I/R injury, has been shown to enhance the regenerative capacity of hepatocytes. However, investigations have always focused on regeneration in the late phase after reperfusion. This study aimed to investigate whether IPC enhances hepatocyte proliferation in the early phase after reperfusion and possible underlying mechanisms. METHODS A total of 90 rats were divided into three groups: hemi-hepatectomy alone (PHx group), 60 minutes of ischemia plus hemi-hepatectomy (I/R group), and a cycle of 10 minutes of alternating I/R prior to 60 minutes of ischemia plus hemi-hepatectomy (IPC group). Each group was divided into five subgroups sacrificed after 0.5, 2, 6, 12 or 24 hours (n=6/subgroup). Subsequently, serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were measured; caspase-3 and proliferating cell nuclear antigen (PCNA) proteins were also determined by Western blotting. Furthermore, PCNA was detected by immunohistochemistry to identify the expression site. RESULTS Serum ALT and AST levels after 2-24 hours of reperfusion in the PHx and IPC groups were remarkably decreased compared to the I/R group, and the serum TNF-alpha was relatively lower. A significant increase of serum IL-6 levels was found in the PHx and IPC groups compared with the I/R group at each time point. Furthermore, PCNA expression was remarkably increased in the IPC group after 6-12 hours of reperfusion, and in the earlier 0.5 and 6 hours time points after reperfusion have shown the massive PCNA-positive hepatocytes. At the same time, the expression of liver p-JNK was higher in the IPC group in the early phase after reperfusion than that of the I/R group and its expression was consistent with the PCNA. CONCLUSION IPC can initiate hepatocyte proliferation in the early phase after ischemia under hemi-hepatectomy, and may be associated with p-JNK expression and triggered by TNF-alpha/IL-6 signals.
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Affiliation(s)
- Li-Ming Jin
- Department of General Surgery, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310003, China
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35
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Fouraschen SMG, Pan Q, de Ruiter PE, Farid WRR, Kazemier G, Kwekkeboom J, Ijzermans JNM, Metselaar HJ, Tilanus HW, de Jonge J, van der Laan LJW. Secreted factors of human liver-derived mesenchymal stem cells promote liver regeneration early after partial hepatectomy. Stem Cells Dev 2012; 21:2410-9. [PMID: 22455365 DOI: 10.1089/scd.2011.0560] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Rapid liver regeneration is required after living-donor liver transplantation and oncologic liver resections to warrant sufficient liver function and prevent small-for-size syndrome. Recent evidence highlights the therapeutic potential of mesenchymal stem cells (MSC) for treatment of toxic liver injury, but whether MSC and their secreted factors stimulate liver regeneration after surgical injury remains unknown. Therefore, the aim of this study is to investigate the effect of human liver-derived MSC-secreted factors in an experimental liver resection model. C57BL/6 mice were subjected to a 70% partial hepatectomy and treated with either concentrated MSC-conditioned culture medium (MSC-CM) or vehicle control. Animals were analyzed for liver and body weight, hepatocyte proliferation, and hepatic gene expression. Effects of MSC-CM on gene expression in a human hepatocyte-like cell line (Huh7 cells) were analyzed using genome-wide gene expression arrays. Liver regeneration was significantly stimulated by MSC-CM as shown by an increase in liver to body weight ratio and hepatocyte proliferation. MSC-CM upregulated hepatic gene expression of cytokines and growth factors relevant for cell proliferation, angiogenesis, and anti-inflammatory responses. In vitro, treatment of Huh7 cells with MSC-CM significantly altered expression levels of ~3,000 genes. Functional analysis revealed strong effects on networks associated with protein synthesis, cell survival, and cell proliferation. This study shows that treatment with MSC-derived factors can promote hepatocyte proliferation and regenerative responses in the early phase after surgical resection. MSC-CM may represent a feasible new strategy to promote liver regeneration in patients undergoing extensive liver resection or after transplantation of small liver grafts.
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Affiliation(s)
- Suomi M G Fouraschen
- Laboratory of Experimental Transplantation and Intestinal Surgery, Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
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Taki-Eldin A, Zhou L, Xie HY, Zheng SS. Liver regeneration after liver transplantation. ACTA ACUST UNITED AC 2012; 48:139-53. [PMID: 22572792 DOI: 10.1159/000337865] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 02/07/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND/PURPOSE The liver has a remarkable capacity to regenerate after injury or resection. The aim of this review is to outline the mechanisms and factors affecting liver regeneration after liver transplantation. METHODS Relevant studies were reviewed using Medline, PubMed and Springer databases. RESULTS A variety of cytokines (such as interleukin-6 and tumor necrosis factor-α), growth factors (like hepatocyte growth factor and transforming growth factor-α) and cells are involved in liver regeneration. Several factors affect liver regeneration after transplantation such as ischemic injury, graft size, immunosuppression, steatosis, donor age and viral hepatitis. CONCLUSION Liver regeneration has been studied for many years. However, further research is essential to reveal the complex processes affecting liver regeneration, which may provide novel strategies in the management of liver transplantation recipients and donors.
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Affiliation(s)
- A Taki-Eldin
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Abshagen K, Eipel C, Vollmar B. A critical appraisal of the hemodynamic signal driving liver regeneration. Langenbecks Arch Surg 2012; 397:579-90. [PMID: 22311102 DOI: 10.1007/s00423-012-0913-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 01/20/2012] [Indexed: 12/25/2022]
Abstract
BACKGROUND Many aspects of the signaling mechanisms involved in the initiation of hepatic regeneration are under current investigation. Nevertheless, the actual mechanisms switching liver regeneration on and off are still unknown. Hemodynamic changes in the liver following partial hepatectomy have been suggested to be a primary stimulus in triggering liver regeneration. Most of the new knowledge about the impact of hemodynamic changes on liver regeneration is both conceptually important and directly relevant to clinical problems. PURPOSE The purpose of this review is therefore to exclusively address the hemodynamic signal driving the liver regeneration process.
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Affiliation(s)
- Kerstin Abshagen
- Institute for Experimental Surgery, University of Rostock, 18055 Rostock, Germany.
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38
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Regulation of signal transduction and role of platelets in liver regeneration. Int J Hepatol 2012; 2012:542479. [PMID: 22811921 PMCID: PMC3395153 DOI: 10.1155/2012/542479] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Accepted: 06/08/2012] [Indexed: 12/18/2022] Open
Abstract
Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factor κB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described.
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Taki-Eldin A, Zhou L, Xie HY, Chen KJ, Zhou WH, Zhang W, Xing CY, Yang Z, Zhang K, Zheng SS. Tri-iodothyronine enhances liver regeneration after living donor liver transplantation in rats. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2011; 18:806-14. [PMID: 21584707 DOI: 10.1007/s00534-011-0397-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Ahmed Taki-Eldin
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Lin Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Hai-Yang Xie
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Kang-jie Chen
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Wu-hua Zhou
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Wu Zhang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Chun-Yang Xing
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Zhe Yang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Kai Zhang
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
| | - Shu-Sen Zheng
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health; First Affiliated Hospital, Zhejiang University School of Medicine; Hangzhou 310003 China
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40
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Molecular mechanism of size control in development and human diseases. Cell Res 2011; 21:715-29. [PMID: 21483452 DOI: 10.1038/cr.2011.63] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
How multicellular organisms control their size is a fundamental question that fascinated generations of biologists. In the past 10 years, tremendous progress has been made toward our understanding of the molecular mechanism underlying size control. Original studies from Drosophila showed that in addition to extrinsic nutritional and hormonal cues, intrinsic mechanisms also play important roles in the control of organ size during development. Several novel signaling pathways such as insulin and Hippo-LATS signaling pathways have been identified that control organ size by regulating cell size and/or cell number through modulation of cell growth, cell division, and cell death. Later studies using mammalian cell and mouse models also demonstrated that the signaling pathways identified in flies are also conserved in mammals. Significantly, recent studies showed that dysregulation of size control plays important roles in the development of many human diseases such as cancer, diabetes, and hypertrophy.
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The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis. EMBO J 2011; 30:1357-75. [PMID: 21407177 DOI: 10.1038/emboj.2011.52] [Citation(s) in RCA: 283] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2010] [Accepted: 01/28/2011] [Indexed: 12/21/2022] Open
Abstract
The endoplasmic reticulum (ER) is the cellular organelle responsible for protein folding and assembly, lipid and sterol biosynthesis, and calcium storage. The unfolded protein response (UPR) is an adaptive intracellular stress response to accumulation of unfolded or misfolded proteins in the ER. In this study, we show that the most conserved UPR sensor inositol-requiring enzyme 1 α (IRE1α), an ER transmembrane protein kinase/endoribonuclease, is required to maintain hepatic lipid homeostasis under ER stress conditions through repressing hepatic lipid accumulation and maintaining lipoprotein secretion. To elucidate physiological roles of IRE1α-mediated signalling in the liver, we generated hepatocyte-specific Ire1α-null mice by utilizing an albumin promoter-controlled Cre recombinase-mediated deletion. Deletion of Ire1α caused defective induction of genes encoding functions in ER-to-Golgi protein transport, oxidative protein folding, and ER-associated degradation (ERAD) of misfolded proteins, and led to selective induction of pro-apoptotic UPR trans-activators. We show that IRE1α is required to maintain the secretion efficiency of selective proteins. In the absence of ER stress, mice with hepatocyte-specific Ire1α deletion displayed modest hepatosteatosis that became profound after induction of ER stress. Further investigation revealed that IRE1α represses expression of key metabolic transcriptional regulators, including CCAAT/enhancer-binding protein (C/EBP) β, C/EBPδ, peroxisome proliferator-activated receptor γ (PPARγ), and enzymes involved in triglyceride biosynthesis. IRE1α was also found to be required for efficient secretion of apolipoproteins upon disruption of ER homeostasis. Consistent with a role for IRE1α in preventing intracellular lipid accumulation, mice with hepatocyte-specific deletion of Ire1α developed severe hepatic steatosis after treatment with an ER stress-inducing anti-cancer drug Bortezomib, upon expression of a misfolding-prone human blood clotting factor VIII, or after partial hepatectomy. The identification of IRE1α as a key regulator to prevent hepatic steatosis provides novel insights into ER stress mechanisms in fatty liver diseases associated with toxic liver injuries.
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Li Y, Hu JJ, Han W, Yu Y. Partial hepatectomy in mice: current status of research and implications for clinical practice. Shijie Huaren Xiaohua Zazhi 2011; 19:275-280. [DOI: 10.11569/wcjd.v19.i3.275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The classic model of partial hepatectomy was first established in the 1930s and played a key role in the research of liver regeneration and liver disease in mammals. Rats and mice are the most commonly used animals for research, but surgery is usually performed in rats. Considering many differences between rats and mice, this paper aims to summarize the crucial points in the surgical procedure for mice and the principles and methods of partial hepatectomy.
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Gonzalez HD, Liu ZW, Cashman S, Fusai GK. Small for size syndrome following living donor and split liver transplantation. World J Gastrointest Surg 2010; 2:389-94. [PMID: 21206720 PMCID: PMC3014520 DOI: 10.4240/wjgs.v2.i12.389] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2010] [Revised: 12/16/2010] [Accepted: 12/20/2010] [Indexed: 02/06/2023] Open
Abstract
The field of liver transplantation is limited by the availability of donor organs. The use of living donor and split cadaveric grafts is one potential method of expanding the donor pool. However, primary graft dysfunction can result from the use of partial livers despite the absence of other causes such as vascular obstruction or sepsis. This increasingly recognised phenomenon is termed “Small-for-size syndrome” (SFSS). Studies in animal models and humans have suggested portal hyperperfusion of the graft combined with poor venous outflow and reduced arterial flow might cause sinusoidal congestion and endothelial dysfunction. Graft related factors such as graft to recipient body weight ratio < 0.8, impaired venous outflow, steatosis > 30% and prolonged warm/cold ischemia time are positively predictive of SFSS. Donor related factors include deranged liver function tests and prolonged intensive care unit stay greater than five days. Child-Pugh grade C recipients are at relatively greater risk of developing SFSS. Surgical approaches to prevent SFSS fall into two categories: those targeting portal hyperperfusion by reducing inflow to the graft, including splenic artery modulation and portacaval shunts; and those aiming to relieve parenchymal congestion. This review aims to examine the controversial diagnosis of SFSS, including current strategies to predict and prevent its occurrence. We will also consider whether such interventions could jeopardize the graft by compromising regeneration.
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Affiliation(s)
- Hector Daniel Gonzalez
- Hector Daniel Gonzalez, Zi Wei Liu, Sophia Cashman, Giuseppe K Fusai, Centre for HPB Surgery and Liver Transplantation, Royal Free Hospital, Pond Street, NW3 2QG, London, United Kingdom
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p66(Shc) has a pivotal function in impaired liver regeneration in aged mice by a redox-dependent mechanism. J Transl Med 2010; 90:1718-26. [PMID: 20567235 DOI: 10.1038/labinvest.2010.119] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Liver regeneration involves complicated processes and is affected by various patho-physiological conditions. This study was designed to examine the molecular mechanisms underlying the aging-associated impairment of liver regeneration. Male C57BL/6J mice were used as young and aged mice (<10 weeks and >20 months old, respectively). These mice were subjected to 70% partial hepatectomy (PH). Liver regeneration and liver injury/stresses were evaluated chronologically after PH. Post-hepatectomy liver regeneration was markedly impaired in aged mice. Though the extent of hepatocyte proliferation in the regenerating liver was similar in aged and young mice, cell growth was absent in aged mice. Oxidative stress (OS) was observed immediately after hepatectomy, followed by marked apoptosis in aged mice. Signaling molecules regarding cell proliferation (mitogen-activated protein kinase, STAT3, p46/52(Shc)) and anti-oxidation (catalase, superoxide dismutase, Ref-1, glutathione peroxidase) were expressed/activated after hepatectomy in livers of both aged and young mice. Akt was not activated in aged-mouse liver, but its expression was similar to that in young mice. p66(Shc), known as an age-/oxidant-associated protein, was strongly phosphorylated. By knocking down p66(Shc), the impairment of liver regeneration was normalized. OS immediately after hepatectomy induced subsequent liver injury (apoptosis), and deletion of p66(Shc) suppressed both OS and hepatocyte apoptosis in the regenerating liver of aged mice. Though we need additional data in other animal models to fully understand the mechanism, p66(Shc) may have a pivotal function in the impairment of liver regeneration in aged mice by triggering OS and subsequent apoptosis. This data may provide a clue to understanding the mechanism underlying the association between aging and the impairment of liver regeneration.
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45
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Atta HM. Gene therapy for liver regeneration: experimental studies and prospects for clinical trials. World J Gastroenterol 2010; 16:4019-30. [PMID: 20731015 PMCID: PMC2928455 DOI: 10.3748/wjg.v16.i32.4019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2009] [Revised: 03/03/2010] [Accepted: 03/10/2010] [Indexed: 02/06/2023] Open
Abstract
The liver is an exceptional organ, not only because of its unique anatomical and physiological characteristics, but also because of its unlimited regenerative capacity. Unfolding of the molecular mechanisms that govern liver regeneration has allowed researchers to exploit them to augment liver regeneration. Dramatic progress in the field, however, was made by the introduction of the powerful tool of gene therapy. Transfer of genetic materials, such as hepatocyte growth factor, using both viral and non-viral vectors has proved to be successful in augmenting liver regeneration in various animal models. For future clinical studies, ongoing research aims at eliminating toxicity of viral vectors and increasing transduction efficiency of non-viral vectors, which are the main drawbacks of these systems. Another goal of current research is to develop gene therapy that targets specific liver cells using receptors that are unique to and highly expressed by different liver cell types. The outcome of such investigations will, undoubtedly, pave the way for future successful clinical trials.
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Liu YX, Jin LM, Zhou L, Xie HY, Jiang GP, Chen H, Zheng SS. Sirolimus attenuates reduced-size liver ischemia-reperfusion injury but impairs liver regeneration in rats. Dig Dis Sci 2010; 55:2255-62. [PMID: 19856103 DOI: 10.1007/s10620-009-1002-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2008] [Accepted: 09/21/2009] [Indexed: 01/02/2023]
Abstract
BACKGROUND Evidence has suggested that immunosuppressive drugs impact ischemia-reperfusion injury. AIMS The purpose of the present study was to evaluate the effect of sirolimus on hepatic injury and regeneration in a rat reduced-size liver ischemia-reperfusion model. METHODS Using a newly developed rat reduced-size liver ischemia-reperfusion injury model, the effects of sirolimus were evaluated by assessing liver cell apoptosis and aspartate aminotransferase, myeloperoxidase, and malondialdehyde levels. In addition, liver regeneration after sirolimus treatment was evaluated by measuring liver weight resumption and by the histological examination of bromodeoxyuridine and proliferating cell nuclear antigen expression. RESULTS Sirolimus significantly decreased liver cell apoptosis as well as tissue myeloperoxidase and malondialdehyde levels, but impaired postischemic liver regeneration. Ischemia-reperfusion-induced elevation of aspartate aminotransferase serum levels was significantly decreased by sirolimus. CONCLUSIONS Despite an impairment of postischemic liver proliferation, sirolimus demonstrated beneficial amelioration of ischemia-reperfusion-induced liver injury in a reduced-size liver model in rats.
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Affiliation(s)
- Yuan-Xing Liu
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, People's Republic of China
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Almeida-Porada G, Zanjani ED, Porada CD. Bone marrow stem cells and liver regeneration. Exp Hematol 2010; 38:574-80. [PMID: 20417684 PMCID: PMC2882990 DOI: 10.1016/j.exphem.2010.04.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 04/07/2010] [Accepted: 04/13/2010] [Indexed: 12/11/2022]
Abstract
Development of new approaches to treat patients with hepatic diseases that can eliminate the need for liver transplantation is imperative. Use of cell therapy as a means of repopulating the liver has several advantages over whole-organ transplantation because it would be less invasive, less immunogenic, and would allow the use, in some instances, of autologous-derived cells. Stem/progenitor cells that would be ideal for liver repopulation would need to have characteristics such as availability and ease of isolation, the ability to be expanded in vitro, ensuring adequate numbers of cells, susceptibility to modification by viral vector transduction/genetic recombination, to correct any underlying genetic defects, and the ability of restoring liver function following transplantation. Bone marrow-derived stem cells, such as hematopoietic, mesenchymal and endothelial progenitor cells possess some or most of these characteristics, making them ideal candidates for liver regenerative therapies. Here, we will summarize the ability of each of these stem cell populations to give rise to functional hepatic elements that could mediate repair in patients with liver damage/disease.
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Affiliation(s)
- Graça Almeida-Porada
- Department of Animal Biotechnology, University of Nevada, Reno, Reno, NV 89557-0104, USA.
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48
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Gennero L, Roos MA, Sperber K, Denysenko T, Bernabei P, Calisti GF, Papotti M, Cappia S, Pagni R, Aimo G, Mengozzi G, Cavallo G, Reguzzi S, Pescarmona GP, Ponzetto A. Pluripotent plasticity of stem cells and liver repopulation. Cell Biochem Funct 2010; 28:178-89. [PMID: 20232487 DOI: 10.1002/cbf.1630] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Different types of stem cells have a role in liver regeneration or fibrous repair during and after several liver diseases. Otherwise, the origin of hepatic and/or extra-hepatic stem cells in reactive liver repopulation is under controversy. The ability of the human body to self-repair and replace the cells and tissues of some organs is often evident. It has been estimated that complete renewal of liver tissue takes place in about a year. Replacement of lost liver tissues is accomplished by proliferation of mature hepatocytes, hepatic oval stem cells differentiation, and sinusoidal cells as support. Hepatic oval cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of epithelial cells found in the liver, hepatocytes, and bile ductular cells. In gastroenterology and hepatology, the first attempts to translate stem cell basic research into novel therapeutic strategies have been made for the treatment of several disorders, such as inflammatory bowel diseases, diabetes mellitus, celiachy, and acute or chronic hepatopaties. In the future, pluripotent plasticity of stem cells will open a variety of clinical application strategies for the treatment of tissue injuries, degenerated organs. The promise of liver stem cells lie in their potential to provide a continuous and readily available source of liver cells that can be used for gene therapy, cell transplant, bio-artificial liver-assisted devices, drug toxicology testing, and use as an in vitro model to understand the developmental biology of the liver.
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Affiliation(s)
- Luisa Gennero
- Department of Internal Medicine, University of Turin, Turin, Italy.
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Therapeutic efficacy of human hepatocyte transplantation in a SCID/uPA mouse model with inducible liver disease. PLoS One 2010; 5:e9209. [PMID: 20174638 PMCID: PMC2823785 DOI: 10.1371/journal.pone.0009209] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2009] [Accepted: 01/24/2010] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Severe Combined Immune Deficient (SCID)/Urokinase-type Plasminogen Activator (uPA) mice undergo liver failure and are useful hosts for the propagation of transplanted human hepatocytes (HH) which must compete with recipient-derived hepatocytes for replacement of the diseased liver parenchyma. While partial replacement by HH has proven useful for studies with Hepatitis C virus, complete replacement of SCID/uPA mouse liver by HH has never been achieved and limits the broader application of these mice for other areas of biomedical research. The herpes simplex virus type-1 thymidine kinase (HSVtk)/ganciclovir (GCV) system is a powerful tool for cell-specific ablation in transgenic animals. The aim of this study was to selectively eliminate murine-derived parenchymal liver cells from humanized SCID/uPA mouse liver in order to achieve mice with completely humanized liver parenchyma. Thus, we reproduced the HSVtk (vTK)/GCV system of hepatic failure in SCID/uPA mice. METHODOLOGY/PRINCIPAL FINDINGS In vitro experiments demonstrated efficient killing of vTK expressing hepatoma cells after GCV treatment. For in vivo experiments, expression of vTK was targeted to the livers of FVB/N and SCID/uPA mice. Hepatic sensitivity to GCV was first established in FVB/N mice since these mice do not undergo liver failure inherent to SCID/uPA mice. Hepatic vTK expression was found to be an integral component of GCV-induced pathologic and biochemical alterations and caused death due to liver dysfunction in vTK transgenic FVB/N and non-transplanted SCID/uPA mice. In SCID/uPA mice with humanized liver, vTK/GCV caused death despite extensive replacement of the mouse liver parenchyma with HH (ranging from 32-87%). Surprisingly, vTK/GCV-dependent apoptosis and mitochondrial aberrations were also localized to bystander vTK-negative HH. CONCLUSIONS/SIGNIFICANCE Extensive replacement of mouse liver parenchyma by HH does not provide a secure therapeutic advantage against vTK/GCV-induced cytotoxicity targeted to residual mouse hepatocytes. Functional support by engrafted HH may be secured by strategies aimed at limiting this bystander effect.
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Abstract
Early studies in hepatocyte turnover and liver regeneration showed that the parenchymal cell, the hepatocyte, was the primary and only cell involved in tissue renewal. However, new studies of liver regeneration, hepatocarcinogenesis, liver transplantation, and various cell lines have shown that a variety of cell types participate in maintaining hepatocyte number and mass and question the dogma of the previous hierarchy of hepatocyte differentiation in vitro and in vivo.
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