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Kasahara N, Teratani T, Doi J, Yokota S, Shimodaira K, Kaneko Y, Ohzawa H, Sakuma Y, Sasanuma H, Fujimoto Y, Urahashi T, Yoshitomi H, Yamaguchi H, Kitayama J, Sata N. Controlled release of hydrogel-encapsulated mesenchymal stem cells-conditioned medium promotes functional liver regeneration after hepatectomy in metabolic dysfunction-associated steatotic liver disease. Stem Cell Res Ther 2024; 15:395. [PMID: 39497124 PMCID: PMC11536549 DOI: 10.1186/s13287-024-03993-w] [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: 05/04/2024] [Accepted: 10/10/2024] [Indexed: 11/06/2024] Open
Abstract
BACKGROUND Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis. METHODS Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV). RESULTS The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division. CONCLUSIONS MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx.
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Affiliation(s)
- Naoya Kasahara
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Takumi Teratani
- Division of Translational Research, Jichi Medical University, Shimotsuke, Japan.
| | - Junshi Doi
- Department of Surgery, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | | | | | - Yuki Kaneko
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyuki Ohzawa
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yasunaru Sakuma
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideki Sasanuma
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yasuhiro Fujimoto
- Department of Transplant Surgery, Nagoya University Hospital, Nagoya, Japan
| | - Taizen Urahashi
- Department of Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | - Hideyuki Yoshitomi
- Department of Surgery, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan
| | | | - Joji Kitayama
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Shimotsuke, Japan
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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Santol J, Pereyra D, Haegele S, Ammon D, Ortmayr G, Pirabe A, Jonas JP, Schuster S, Kim S, Nguyen T, Gruenberger T, Assinger A, Starlinger P. The Ratio of Activin A and Follistatin-Like 3 Is Associated With Posthepatectomy Liver Failure and Morbidity in Patients Undergoing Liver Resection. GASTRO HEP ADVANCES 2023; 2:642-651. [PMID: 39129875 PMCID: PMC11307668 DOI: 10.1016/j.gastha.2023.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 02/28/2023] [Indexed: 08/13/2024]
Abstract
Background and Aims Activin A is a key regulator in liver regeneration, but data evaluating its role in humans after hepatic surgery are limited. In this study we explore the predictive role of circulating activin A, its antagonist follistatin-like 3 (FSTL-3), and their ratio for posthepatectomy liver failure (PHLF) and monitor their levels after surgery, to evaluate their role in human liver regeneration. Methods Activin A and FSTL-3 levels were assessed in 59 patients undergoing liver surgery. Using receiver operating characteristic analysis, we evaluated the predictive potential of activin A, FSTL-3, and their ratio. Results While perioperative dynamics of activin A and FSTL3 were significantly affected by hepatic resection (activin A P = .045, FSTL-3 P = .005), their functionally relevant ratio did not significantly change (P = .528). Neither activin A nor FSTL-3 alone but only their ratio exhibited a significant predictive potential for PHLF (area under the curve: 0.789, P = .038). Patients with low preoperative activin A/FSTL-3 ratio were found to more frequently suffer from PHLF (0.017) and morbidity (0.005). Conclusion Activin A/FSTL-3 ratio predicts PHLF and morbidity. Its significance in preoperative patient assessment needs to be further validated in larger, independent cohorts.
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Affiliation(s)
- Jonas Santol
- Department of Surgery, Vienna Health Network, HPB Center, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - David Pereyra
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefanie Haegele
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Daphni Ammon
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Gregor Ortmayr
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Anita Pirabe
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jan Philipp Jonas
- Department of Surgery, Vienna Health Network, HPB Center, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
- Department of Visceral and Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Stefan Schuster
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Sarang Kim
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Toni Nguyen
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, Vienna Health Network, HPB Center, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Alice Assinger
- Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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Tseng FY, Chen YT, Chi YC, Chen PL, Yang WS. Serum Levels of Follistatin Are Positively Associated With Serum-Free Thyroxine Levels in Patients With Hyperthyroidism or Euthyroidism. Medicine (Baltimore) 2016; 95:e2661. [PMID: 26844494 PMCID: PMC4748911 DOI: 10.1097/md.0000000000002661] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Follistatin is a glycoprotein with various biologic functions that plays a role in adipocyte differentiation, muscle stimulation, anti-inflammation, and energy homeostasis. Thyroid hormones influence energy expenditure, glucose, and lipid metabolism. The association between serum follistatin level and thyroid function statuses has seldom been evaluated.The objectives of this study were to compare serum follistatin concentrations in different thyroid function statuses and to evaluate the associations between serum follistatin and free thyroxine (fT4) levels.In this study, 30 patients with hyperthyroidism (HY group) and 30 euthyroid individuals (EU group) were recruited. The patients of HY group were treated with antithyroid regimens as clinically indicated, whereas no medication was given to EU group. The demographic and anthropometric characteristics, biochemical data, serum levels of follistatin, and thyroid function of both groups at baseline and at the 6th month were compared. Data of all patients were pooled for the analysis of the associations between the levels of follistatin and fT4.At baseline, the HY group had significantly higher serum follistatin levels than the EU group (median [Q1, Q3]: 1.81 [1.33, 2.78] vs 1.13 [0.39, 1.45] ng/mL, P < 0.001). When treated with antithyroid regimens, the follistatin serum levels in HY group decreased to 1.54 [1.00, 1.88] ng/mL at the 6th month. In all patients, the serum levels of follistatin were positively associated with fT4 levels at baseline (β = 0.54, P = 0.005) and at the 6th month (β = 0.59, P < 0.001). The association between follistatin and fT4 levels remained significant in the stepwise multivariate regression analysis, both initially and at the 6th month.In comparison to the EU group, patients with hyperthyroidism had higher serum follistatin levels, which decreased after receiving antithyroid treatment. In addition, the serum follistatin concentrations were positively associated with serum fT4 levels in patients with hyperthyroidism or euthyroidism.
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Affiliation(s)
- Fen-Yu Tseng
- From the Division of Endocrinology & Metabolism, Department of Internal Medicine, National Taiwan University Hospital (F-YT, P-LC, W-SY); Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University (Y-TC, Y-CC, W-SY); Department of Medical Genetics, National Taiwan University Hospital, National Taiwan University (P-LC); and Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan (P-LC)
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de Mello F, Streit DP, Sabin N, Gabillard JC. Identification of TGF-β, inhibin βA and follistatin paralogs in the rainbow trout genome. Comp Biochem Physiol B Biochem Mol Biol 2014; 177-178:46-55. [DOI: 10.1016/j.cbpb.2014.07.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 07/22/2014] [Accepted: 07/25/2014] [Indexed: 11/15/2022]
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Stochastic control of proliferation and differentiation in stem cell dynamics. J Math Biol 2014; 71:883-901. [PMID: 25319118 DOI: 10.1007/s00285-014-0835-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 10/31/2012] [Indexed: 12/24/2022]
Abstract
In self-renewing tissues, cell lineages consisting of stem cell and classes of daughter cells are the basic units which are responsible for the correct functioning of the organ. Cell proliferation and differentiation in lineages is thought to be mediated by feedback signals. In the simplest case a lineage is comprised of stem cells and differentiated cells. We create a model where stem cell proliferation and differentiation are controlled by the size of cell populations by means of a negative feedback loop. This two-dimensional Markov process allows for an analytical solution for the mean numbers and variances of stem and daughter cells. The mean values and the amounts of variation in cell numbers can be tightly regulated by the parameters of the control loop.
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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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Chen L, Zhang W, Liang HF, Zhou QD, Ding ZY, Yang HQ, Liu WB, Wu YH, Man Q, Zhang BX, Chen XP. Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells. Cell Commun Signal 2014; 12:18. [PMID: 24628936 PMCID: PMC3995548 DOI: 10.1186/1478-811x-12-18] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Accepted: 03/08/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Activin A, an important member of transforming growth factor-β superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation. RESULTS Using the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model. CONCLUSION Activin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells.
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Affiliation(s)
- Lin Chen
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Zhang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hui-fang Liang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Qiao-dan Zhou
- Department of Nephrology, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Ze-yang Ding
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Hong-qiang Yang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College of Shihezi University, Shihezi, China
| | - Wei-bo Liu
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yan-hui Wu
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Quan Man
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Bi-xiang Zhang
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-ping Chen
- Hepatic surgery centre, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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Cleveland BM, Weber GM. Ploidy effects on genes regulating growth mechanisms during fasting and refeeding in juvenile rainbow trout (Oncorhynchus mykiss). Mol Cell Endocrinol 2014; 382:139-149. [PMID: 24076188 DOI: 10.1016/j.mce.2013.09.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 09/17/2013] [Accepted: 09/18/2013] [Indexed: 11/19/2022]
Abstract
Diploid and triploid rainbow trout weighing approximately 3g were either fed for five weeks, or feed deprived for one week, followed by refeeding. During feed deprivation gastrointestinal somatic index decreased in diploids, but not triploids, and during refeeding, carcass growth rate recovered more quickly in triploids. Although not affected by ploidy, liver ghr2 and igfbp2b expression increased and igfbp1b decreased in fasted fish. Effects of ploidy on gene expression indicate potential mechanisms associated with improved recovery growth in triploids, which include decreased hepatic igfbp expression, which could influence IGF-I bioavailability, differences in tissue sensitivity to TGFbeta ligands due to altered tgfbr and smad expression, and differences in expression of muscle regulatory genes (myf5, mstn1a, and mstn1b). These data suggest that polyploidy influences the expression of genes critical to muscle development and general growth regulation, which may explain why triploid fish recover from nutritional insult better than diploid fish.
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Affiliation(s)
- Beth M Cleveland
- National Center for Cool and Cold Water Aquaculture, USDA/ARS, 11861 Leetown Rd, Kearneysville, WV 25427, United States.
| | - Gregory M Weber
- National Center for Cool and Cold Water Aquaculture, USDA/ARS, 11861 Leetown Rd, Kearneysville, WV 25427, United States
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Sun Z, Komarova NL. Stochastic modeling of stem-cell dynamics with control. Math Biosci 2012; 240:231-40. [PMID: 22960597 PMCID: PMC3921979 DOI: 10.1016/j.mbs.2012.08.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 08/14/2012] [Accepted: 08/20/2012] [Indexed: 12/12/2022]
Abstract
Tissue development and homeostasis are thought to be regulated endogenously by control loops that ensure that the numbers of stem cells and daughter cells are maintained at desired levels, and that the cell dynamics are robust to perturbations. In this paper we consider several classes of stochastic models that describe stem/daughter cell dynamics in a population of constant size, which are generalizations of the Moran process that include negative control loops that affect differentiation probabilities for stem cells. We present analytical solutions for the steady-state expectations and variances of the numbers of stem and daughter cells; these results remain valid for non-constant cell populations. We show that in the absence of differentiation/proliferation control, the number of stem cells is subject to extinction or overflow. In the presence of linear control, a steady state may be maintained but no tunable parameters are available to control the mean and the spread of the cell population sizes. Two types of nonlinear control considered here incorporate tunable parameters that allow specification of the expected number of stem cells and also provide control over the size of the standard deviation. We show that under a hyperbolic control law, there is a trade-off between minimizing standard deviations and maintaining the system robustness against external perturbations. For the Hill-type control, the standard deviation is inversely proportional to the Hill coefficient of the control loop. Biologically this means that ultrasensitive response that is observed in a number of regulatory loops may have evolved in order to reduce fluctuations while maintaining the desired population levels.
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Affiliation(s)
- Zheng Sun
- Department of Mathematics, University of California Irvine, Irvine, CA 92617
| | - Natalia L. Komarova
- Department of Mathematics, University of California Irvine, Irvine, CA 92617
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Voumvouraki A, Notas G, Koulentaki M, Georgiadou M, Klironomos S, Kouroumalis E. Increased serum activin-A differentiates alcoholic from cirrhosis of other aetiologies. Eur J Clin Invest 2012; 42:815-22. [PMID: 22304651 DOI: 10.1111/j.1365-2362.2012.02647.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Activin-A is a molecule of the TGF superfamily, implicated in liver fibrosis, regeneration and stem cell differentiation. However, data on activins in liver diseases are few. We therefore studied serum levels of activin-A in chronic liver diseases. To identify the origin of activin-A, levels in the hepatic vein were also estimated. MATERIALS AND METHODS Nineteen controls and 162 patients participated in the study: 39 with hepatocellular carcinoma (HCC: 19 viral associated and 20 alcohol associated), 18 with chronic hepatitis C (CHC), 47 with primary biliary cirrhosis (26 PBC stage I-II and 21 stage IV), 22 with alcoholic cirrhosis (AC, hepatic vein blood available in 16), 20 with HCV cirrhosis (hepatic vein blood available in 18) and 16 patients with alcoholic fatty liver with mild to moderate fibrosis but no cirrhosis. RESULTS Activin-A levels were significantly increased (P < 0·001) in serum of patients with AC (median 673 pg/mL, range 449-3279), compared with either controls (149 pg/mL, 91-193) or patients with viral cirrhosis (189 pg/mL, 81-480), CHC (142 pg/mL, 65-559) PBC stage I-II (100 pg/mL, 59-597) and PBC stage IV (104 pg/mL, 81-579). Only patients with AC-associated HCC had significantly increased levels of activin-A (2403 pg/mL, 1561-7220 pg/mL). Activin-A serum levels could accurately discriminate AC from cirrhosis of other aetiologies and noncirrhotic alcoholic fatty liver with fibrosis. CONCLUSIONS Increased serum levels of activin-A only in patients with alcohol-related cirrhosis or HCC suggest a possible role of this molecule in the pathophysiology of AC. Further research is warranted to elucidate its role during the profibrotic process and its possible clinical applications.
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Affiliation(s)
- Argyro Voumvouraki
- University Hospital Department of Gastroenterology, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
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Ooe H, Chen Q, Kon J, Sasaki K, Miyoshi H, Ichinohe N, Tanimizu N, Mitaka T. Proliferation of rat small hepatocytes requires follistatin expression. J Cell Physiol 2012; 227:2363-70. [PMID: 21826650 DOI: 10.1002/jcp.22971] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Small hepatocytes (SHs) are a subpopulation of hepatocytes that have high growth potential in culture and can differentiate into mature hepatocytes (MHs). The activin (Act)/follistatin (Fst) system critically contributes to homeostasis of cell growth in the normal liver. ActA and ActB consist of two disulfide-linked Inhibin (Inh)β subunits, InhβA and InhβB, respectively. Fst binds to Act and blocks its bioactivity. In the present study we carried out the experiments to clarify how Fst regulates the proliferation of SHs. The gene expression was analyzed using DNA microarray analysis, reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR, and protein expression was examined by western blots, immunocytochemistry, and enzyme-linked immunosorbent assay. RT-PCR showed that Fst expression was high in SHs and low in MHs. Although the ActA expression was opposite to that of Fst, ActB expression was high in SHs and low in MHs and increased with time in culture. Fst protein was detected in the cytoplasm of SHs and secreted into the culture medium. ActB protein was also secreted into the medium. Although the exogenous administration of ActA and ActB apparently suppressed the proliferation of SHs, apoptosis of SHs was not induced by treatment with ActA or ActB. On the other hand, Fst treatment did not affect the colony formation of SHs but prevented the inhibitory effect of ActA. Neutralization by the anti-Fst antibody resulted in the suppression of DNA synthesis in SHs, and small hairpin RNA against Fst suppressed the expansion of SH colonies. In conclusion, Fst expression is necessary for the proliferation of SHs.
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Affiliation(s)
- Hidekazu Ooe
- Department of Tissue Development and Regeneration, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan
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Chen H, Sun Y, Dong R, Yang S, Pan C, Xiang D, Miao M, Jiao B. Mir-34a is upregulated during liver regeneration in rats and is associated with the suppression of hepatocyte proliferation. PLoS One 2011; 6:e20238. [PMID: 21655280 PMCID: PMC3105003 DOI: 10.1371/journal.pone.0020238] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 04/16/2011] [Indexed: 12/14/2022] Open
Abstract
Background MicroRNAs are a class of small regulatory RNAs that modulate a variety of biological processes, including cellular differentiation, apoptosis, metabolism and proliferation. This study aims to explore the effect of miR-34a in hepatocyte proliferation and its potential role in liver regeneration termination. Methodology/Principal Finding MiR-34a was highly induced after partial hepatectomy. Overexpression of miR-34a in BRL-3A cells could significantly inhibit cell proliferation and down-regulate the expression of inhibin βB (INHBB) and Met. In BRL-3A cells, INHBB was identified as a direct target of miR-34a by luciferase reporter assay. More importantly, INHBB siRNA significantly repressed cell proliferation. A decrease of INHBB and Met was detected in regenerating liver. Conclusion/Significance MiR-34a expression was upregulated during the late phase of liver regeneration. MiR-34a-mediated regulation of INHBB and Met may collectively contribute to the suppression of hepatocyte proliferation.
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Affiliation(s)
- Huan Chen
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
| | - Yimin Sun
- National Engineering Research Center for Beijing Biochip Technology, Beijing, China
| | - Ruiqi Dong
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
| | - Shengsheng Yang
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
| | - Chuanyong Pan
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
| | - Dao Xiang
- Department of Cellular Biology, Second Military Medical University, Shanghai, China
| | - Mingyong Miao
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
- * E-mail: (BJ); (MM)
| | - Binghua Jiao
- Department of Biochemistry and Molecular Biology, Second Military Medical University, Shanghai, China
- * E-mail: (BJ); (MM)
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14
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Kanamoto M, Shimada M, Morine Y, Yoshizumi T, Imura S, Ikegami T, Mori H, Arakawa Y. Beneficial effects of follistatin in hepatic ischemia-reperfusion injuries in rats. Dig Dis Sci 2011; 56:1075-81. [PMID: 20824496 DOI: 10.1007/s10620-010-1401-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Accepted: 08/12/2010] [Indexed: 12/09/2022]
Abstract
BACKGROUND Ischemia-reperfusion injury has been demonstrated in a variety of clinical settings. The morbidity associated with liver transplantation and major hepatic resections is partly a result of ischemia-reperfusion injury. Follistatin, an activin-binding protein, binds to activins and subsequently blocks their action. It was reported that blockade of the action of activin with administration of follistatin accelerates recovery from ischemia renal injury. This study was conducted to investigate the involvement of the activin-follistatin system in hepatic ischemia-reperfusion injury. METHODS Total hepatic ischemia for 30 min was performed followed by reperfusion in a rat model. Rats were divided into two groups: a follistatin group and a control group. Follistatin (1 μg/body), which is an activin-binding protein, was administered at the time of reperfusion. RESULTS Though 80% of animals survived in the follistatin group, four of five animals died in the control group within 3 days after reperfusion (p<0.05). AST was significantly lower at 3 h after reperfusion in the follistatin group (p<0.05). LDH was also lower at 6 h after reperfusion in the follistatin group (p<0.05). Follistatin inhibited the mRNA expression of the βA subunit of activin. Moreover, the expression of IL-6, which is an inflammatory cytokine, was suppressed at 6 h after reperfusion in the follistatin group (p<0.05). CONCLUSIONS The present study demonstrated that treatment with follistatin reduced the expression of IL-6 and activin resulting in beneficial support for hepatic ischemia-reperfusion injuries.
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Affiliation(s)
- Mami Kanamoto
- Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto, Tokushima, 770-8503, Japan.
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15
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Zheng ZY, Weng SY, Yu Y. Signal molecule-mediated hepatic cell communication during liver regeneration. World J Gastroenterol 2009; 15:5776-83. [PMID: 19998497 PMCID: PMC2791269 DOI: 10.3748/wjg.15.5776] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [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
Liver regeneration is a complex and well-orchestrated process, during which hepatic cells are activated to produce large signal molecules in response to liver injury or mass reduction. These signal molecules, in turn, set up the connections and cross-talk among liver cells to promote hepatic recovery. In this review, we endeavor to summarize the network of signal molecules that mediates hepatic cell communication in the regulation of liver regeneration.
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16
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Kreidl E, Oztürk D, Metzner T, Berger W, Grusch M. Activins and follistatins: Emerging roles in liver physiology and cancer. World J Hepatol 2009; 1:17-27. [PMID: 21160961 PMCID: PMC2999257 DOI: 10.4254/wjh.v1.i1.17] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2009] [Revised: 09/10/2009] [Accepted: 09/17/2009] [Indexed: 02/06/2023] Open
Abstract
Activins are secreted proteins belonging to the TGF-β family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.
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Affiliation(s)
- Emanuel Kreidl
- Emanuel Kreidl, Deniz Öztürk, Thomas Metzner, Walter Berger, Michael Grusch, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, Vienna A-1090, Austria
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17
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Arakawa Y, Shimada M, Uchiyama H, Ikegami T, Yoshizumi T, Imura S, Morine Y, Kanemura H. Beneficial effects of splenectomy on massive hepatectomy model in rats. Hepatol Res 2009; 39:391-7. [PMID: 19889050 DOI: 10.1111/j.1872-034x.2008.00469.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Possible spleno-hepatic relationships during hepatectomy remain unclear. The purpose of this study was to investigate the impact of splenectomy during massive hepatectomy in rats. METHODS Rats were divided into the following two groups: 90% hepatectomy (Hx group), hepatectomy with splenectomy (Hx+Sp group). The following parameters were evaluated; survival rate, biochemical parameters, quantitative RT-PCR for hemeoxygenase-1 (HO-1) and tumor necrosing factor alpha (TNFalpha), immunohistochemical staining for HO-1, proliferating cell nuclear antigen labeling index and liver weights. RESULTS The survival rate after massive hepatectomy significantly improved in Hx+Sp group as well as serum biochemical parameters, compared with Hx group (P < 0.05). HO-1 positive hepatocytes and its mRNA expression significantly increased and TNFalpha mRNA expression significantly decreased in Hx+Sp group compared with Hx group (P < 0.05). Moreover, liver regeneration was significantly accelerated at 48 and 72 h after hepatectomy in Hx+Sp group. CONCLUSIONS Splenectomy had beneficial effects on massive hepatectomy by ameliorating liver injuries and promoting preferable liver regeneration.
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Affiliation(s)
- Yusuke Arakawa
- Department of Surgery, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan
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18
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Deli A, Kreidl E, Santifaller S, Trotter B, Seir K, Berger W, Schulte-Hermann R, Rodgarkia-Dara C, Grusch M. Activins and activin antagonists in hepatocellular carcinoma. World J Gastroenterol 2008; 14:1699-709. [PMID: 18350601 PMCID: PMC2695910 DOI: 10.3748/wjg.14.1699] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [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
In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo- or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.
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19
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Sahin MB, Schwartz RE, Buckley SM, Heremans Y, Chase L, Hu WS, Verfaillie CM. Isolation and characterization of a novel population of progenitor cells from unmanipulated rat liver. Liver Transpl 2008; 14:333-45. [PMID: 18306374 DOI: 10.1002/lt.21380] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Widespread use of liver transplantation in the treatment of hepatic diseases is restricted by the limited availability of donated organs. One potential solution to this problem would be isolation and propagation of liver progenitor cells or stem cells. Here, we report on the isolation of a novel progenitor cell population from unmanipulated (that is, no prior exposure to chemicals and no injury) adult rat liver. Rat liver cells were cultured following a protocol developed in our laboratory to generate a unique progenitor cell population called liver-derived progenitor cells (LDPCs). LDPCs were analyzed by fluorescence-activated cell sorting, real-time polymerase chain reaction (RT-PCR), immunostaining and microarray gene expression. LDPCs were also differentiated into hepatocytes and biliary epithelium in vitro and examined for mature hepatic markers and urea and albumin production. These analyses showed that, LDPCs expressed stem cell markers such as cluster domain (CD)45, CD34, c-kit, and Thy 1, similar to hematopoietic stem cells, as well as endodermal/hepatic markers such as hepatocyte nuclear factor (HNF)3beta, hematopoietically-expressed homeobox gene-1, c-met, and transthyretin. LDPCs were negative for OV-6, cytokeratins (CKs), albumin, and HNF1alpha. The microarray gene expression profile demonstrated that they showed some similarities to known liver progenitor/stem cells such as oval cells. In addition, LDPCs differentiated into functional hepatocytes in vitro as shown by albumin expression and urea production. In conclusion, LDPCs are a population of unique liver progenitors that can be generated from unmanipulated adult liver, which makes them potentially useful for clinical applications, especially for cell transplantation in the treatment of liver diseases.
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Affiliation(s)
- M Behnan Sahin
- Stem Cell Institute and Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
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20
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Zhang HJ, Liu ZH, Chen FF, Ma D, Zhou J, Tai GX. Activin receptor-interacting protein 2 expression and its biological function in mouse hepatocytes. Shijie Huaren Xiaohua Zazhi 2008; 16:350-355. [DOI: 10.11569/wcjd.v16.i4.350] [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
AIM: To investigate the activin receptor-interacting protein 2 (ARIP2) expression and its biological function in hepatocytes.
METHODS: Expression of ARIP2 in mouse liver tissue and hepatoma cell line Hepal-6 cells was detected by Western blot, immunohistochemistry and cytochemical staining. Effect of ARIP2 on activin-induced gene transcription was analyzed using CAGA-lux plasmid. Effect of over-expression of ARIP2 on the proliferation of Hepal-6 cells was assayed with MTT method.
RESULTS: ARIP2 was expressed in mouse liver tissue and Hepal-6 cells. The expression of ARIP2 in activin A-stimulated Hepal-6 cells was increased in a time-dependent manner, and peaked at 24 h. There was a significant difference in the expression level of ARIP2 on Hepal-6 cells at 12 and 24 h in contrast with the control group (1.01 ± 0.16, 1.62 ± 0.26 vs 0.82 ± 0.11, P < 0.05, P < 0.01). pcDNA3-ARIP2-transfected Hepal-6 cells obviously suppressed the gene transcription induced by activin A. MTT assay displayed that activin A (5 μg/L and 10 μg/L) remarkably inhibited the proliferation of Hepal-6 cells, the A570 nm value was 1.59 ± 0.03 and 1.49 ± 0.04 vs 1.79±0.07, respectively (P < 0.05, P < 0.01). ARIP2 over-expression in Hepal-6 cells significantly blocked the inhibitory effects of activin A (5 μg/L and 10 μg/L) on the proliferation of Hepal-6 cells.
CONCLUSION: ARIP2 can be expected to become a regulation target of genes in treatment of liver injury induced by activin.
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21
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Aoki F, Kojima I. Therapeutic potential of follistatin to promote tissue regeneration and prevent tissue fibrosis. Endocr J 2007; 54:849-54. [PMID: 17938504 DOI: 10.1507/endocrj.kr07e-001] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Affiliation(s)
- Fumiaki Aoki
- Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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22
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Zhang HJ, Tai GX, Zhou J, Ma D, Liu ZH. Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV. World J Gastroenterol 2007; 13:5501-5. [PMID: 17907296 PMCID: PMC4171287 DOI: 10.3748/wjg.v13.i41.5501] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the regulation of activin receptor-interacting protein 2 (ARIP2) expression and its possible relationships with collagen type IV (collagen IV) in mouse hepatoma cell line Hepal-6 cells.
METHODS: The ARIP2 mRNA expression kinetics in Hepal-6 cells was detected by RT-PCR, and its regulation factors were analyzed by treatment with signal transduction activators such as phorbol 12-myristate 13-acetate (PMA), forskolin and A23187. After pcDNA3-ARIP2 was transfected into Hepal-6 cells, the effects of ARIP2 overexpression on activin type II receptor (ActRII) and collagen IV expression were evaluated.
RESULTS: The expression levels of ARIP2 mRNA in Hapel-6 cells were elevated in time-dependent manner 12 h after treatment with activin A and endotoxin LPS, but not changed evidently in the early stage of stimulation (2 or 4 h). The ARIP2 mRNA expression was increased after stimulated with signal transduction activators such as PMA and forskolin in Hepal-6 cells, whereas decreased after treatment with A23187 (25.3% ± 5.7% vs 48.1% ± 3.6%, P < 0.01). ARIP2 overexpression could remarkably suppress the expression of ActRIIA mRNA in dose-dependent manner, but has no effect on ActRIIB in Hepal-6 cells induced by activin A. Furthermore, we have found that overexpression of ARIP2 could inhibit collagen IV mRNA and protein expressions induced by activin A in Hapel-6 cells.
CONCLUSION: These findings suggest that ARIP2 expression can be influenced by various factors. ARIP2 may participate in the negative feedback regulation of signal transduction in the late stage by affecting the expression of ActRIIA and play an important role in regulation of development of liver fibrosis induced by activin.
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MESH Headings
- Activin Receptors, Type II/genetics
- Activin Receptors, Type II/metabolism
- Activins/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Adenylyl Cyclases/metabolism
- Animals
- Calcimycin/pharmacology
- Calcium/metabolism
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Cell Line, Tumor
- Colforsin/pharmacology
- Collagen Type IV/genetics
- Collagen Type IV/metabolism
- Enzyme Activators/pharmacology
- Gene Expression Regulation, Neoplastic/drug effects
- Ionophores/pharmacology
- Kinetics
- Lipopolysaccharides/pharmacology
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Mice
- Protein Kinase C/metabolism
- RNA, Messenger/metabolism
- Signal Transduction/drug effects
- Signal Transduction/genetics
- Tetradecanoylphorbol Acetate/pharmacology
- Transfection
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Affiliation(s)
- Hong-Jun Zhang
- Department of Immunology, School of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin Province, China
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Yamada S, Yamamoto Y, Nagasawa M, Hara A, Kodera T, Kojima I. In vitro transdifferentiation of mature hepatocytes into insulin-producing cells. Endocr J 2006; 53:789-95. [PMID: 16983179 DOI: 10.1507/endocrj.k06-116] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Adenovirus-mediated gene transfer of pancreatic duodenal homeobox transcription factor PDX-1, especially its super-active version (PDX-1/VP16), induces the expression of pancreatic hormones in murine liver and reverses streptozotocin-induced hyperglycemia. Histological analyses suggest that hepatocytes are the major source of insulin-producing cells by PDX-1 gene transfer, although the conversion of cultured hepatocytes into insulin-producing cells remains to be elucidated. The present study was conducted to address this issue. Hepatocytes were isolated from adult rats. Then, PDX-1 or PDX-1/VP16 gene was introduced by using adenovirus vector. Two days later, the expression of insulin was detected at mRNA and protein levels. Transfection of PDX-1/VP16 was more efficient in converting hepatocytes to insulin-producing cells. Immunoreactivity of albumin was downregulated in transdifferentiated cells and some of them almost completely lost albumin expression. During the course of transdifferentiation, upregulation of mRNA for CK19 and alpha-fetoprotein was observed. When cultured in collagen-1 gel sandwich configuration, hepatocytes maintained their mature phenotype and did not proliferate. In this condition, transfer of PDX-1/VP16 also induced the expression of insulin. These results clearly indicate that hepatocytes possess a potential to transdifferentiate into insulin-producing cells in vitro.
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Affiliation(s)
- Satoko Yamada
- Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
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24
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Rodgarkia-Dara C, Vejda S, Erlach N, Losert A, Bursch W, Berger W, Schulte-Hermann R, Grusch M. The activin axis in liver biology and disease. Mutat Res 2006; 613:123-37. [PMID: 16997617 DOI: 10.1016/j.mrrev.2006.07.002] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2006] [Revised: 07/27/2006] [Accepted: 07/27/2006] [Indexed: 12/22/2022]
Abstract
Activins are a closely related subgroup within the TGFbeta superfamily of growth and differentiation factors. They consist of two disulfide-linked beta subunits. Four mammalian activin beta subunits termed beta(A), beta(B), beta(C), and beta(E), respectively, have been identified. Activin A, the homodimer of two beta(A) subunits, has important regulatory functions in reproductive biology, embryonic development, inflammation, and tissue repair. Several intra- and extracellular antagonists, including the activin-binding proteins follistatin and follistatin-related protein, serve to fine-tune activin A activity. In the liver there is compelling evidence that activin A is involved in the regulation of cell number by inhibition of hepatocyte replication and induction of apoptosis. In addition, activin A stimulates extracellular matrix production in hepatic stellate cells and tubulogenesis of sinusoidal endothelial cells, and thus contributes to restoration of tissue architecture during liver regeneration. Accumulating evidence from animal models and from patient data suggests that deregulation of activin A signaling contributes to pathologic conditions such as hepatic inflammation and fibrosis, acute liver failure, and development of liver cancer. Increased production of activin A was suggested to be a contributing factor to impaired hepatocyte regeneration in acute liver failure and to overproduction of extracellular matrix in liver fibrosis. Recent evidence suggests that escape of (pre)neoplastic hepatocytes from growth control by activin A through overexpression of follistatin and reduced activin production contributes to hepatocarcinogenesis. The role of the activin subunits beta(C) and beta(E), which are both highly expressed in hepatocytes, is still quite incompletely understood. Down-regulation in liver tumors and a growth inhibitory function similar to that of beta(A) has been shown for beta(E). Contradictory results with regard to cell proliferation have been reported for beta(C). The profound involvement of the activin axis in liver biology and in the pathogenesis of severe hepatic diseases suggests activin as potential target for therapeutic interventions.
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Affiliation(s)
- Chantal Rodgarkia-Dara
- Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
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