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Konstantis G, Tsaousi G, Pourzitaki C, Kitsikidou E, Magouliotis DE, Wiener S, Zeller AC, Willuweit K, Schmidt HH, Rashidi-Alavijeh J. Efficacy of Granulocyte Colony-Stimulating Factor in Acute on Chronic Liver Failure: A Systematic Review and Survival Meta-Analysis. J Clin Med 2023; 12:6541. [PMID: 37892679 PMCID: PMC10607065 DOI: 10.3390/jcm12206541] [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: 09/04/2023] [Revised: 10/02/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Acute-on-chronic liver failure (ACLF) mostly occurs when there is an acute insult to the liver in patients with pre-existing liver disease, and it is characterized by a high mortality rate. Various therapeutic approaches have been used thus far, with orthotopic liver transplantation being the only definitive cure. Clinical trials and meta-analyses have investigated the use of granulocyte colony-stimulating factor (G-CSF) to mobilize bone marrow-derived stem cells. Some studies have suggested that G-CSF may have a significant role in the management and survival of patients with ACLF. However, the results are conflicting, and the efficacy of G-CSF still needs to be confirmed. AIM The aim was to assess the efficacy of G-CSF in patients with ACLF. METHODS Electronic databases were searched until May 2023 for randomized controlled trials investigating the use of G-CSF in adult patients with ACLF. Outcome measures were the effects of G-CSF on overall survival, changes in liver disease severity scores, complications of cirrhosis, other G-CSF-related adverse effects, and all-cause mortality. The study's protocol has been registered with Prospero (CRD42023420273). RESULTS Five double-blind randomized controlled trials involving a total of 421 participants met the inclusion criteria. The use of G-CSF demonstrated a significant effect on overall survival (HR 0.63, 95% CI 0.41 to 0.95, and I2 48%), leading to a decreased mortality (LogOR-0.97, 95% CI -1.57 to -0.37, and I2 37.6%) and improved Model for End-Stage Liver Disease (MELD) scores (SMD -0.87, 95% CI -1.62 to -0.13, and I2 87.3%). There was no correlation between the improvement of the Child-Pugh score and the use of G-CSF(SMD -2.47, 95% CI -5.78 to 0.83, and I2 98.1%). The incidence of complications of cirrhosis did not decrease significantly with G-CSF treatment (rate ratio 0.51, 95% CI 0.26 to 1.01, and I2 90%). A qualitative synthesis showed that the use of G-CSF is safe. CONCLUSIONS The administration of G-CSF has demonstrated a positive impact on overall survival, liver function, and the MELD score. The presence of heterogeneity in the included studies prohibits conclusive recommendations.
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Affiliation(s)
- Georgios Konstantis
- Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Georgia Tsaousi
- Department of Anesthesiology and ICU, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Chryssa Pourzitaki
- Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Elisavet Kitsikidou
- Department of Internal Medicine, Evangelical Hospital Dusseldorf, 40217 Dusseldorf, Germany;
| | | | - Sebastian Wiener
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Amos Cornelius Zeller
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Katharina Willuweit
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Hartmut H. Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
| | - Jassin Rashidi-Alavijeh
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 40219 Essen, Germany
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Xu G, Fatima A, Breitbach M, Kuzmenkin A, Fügemann CJ, Ivanyuk D, Kim KP, Cantz T, Pfannkuche K, Schoeler HR, Fleischmann BK, Hescheler J, Šarić T. Electrophysiological Properties of Tetraploid Cardiomyocytes Derived from Murine Pluripotent Stem Cells Generated by Fusion of Adult Somatic Cells with Embryonic Stem Cells. Int J Mol Sci 2023; 24:ijms24076546. [PMID: 37047520 PMCID: PMC10095437 DOI: 10.3390/ijms24076546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 03/20/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Most cardiomyocytes (CMs) in the adult mammalian heart are either binucleated or contain a single polyploid nucleus. Recent studies have shown that polyploidy in CMs plays an important role as an adaptive response to physiological demands and environmental stress and correlates with poor cardiac regenerative ability after injury. However, knowledge about the functional properties of polyploid CMs is limited. In this study, we generated tetraploid pluripotent stem cells (PSCs) by fusion of murine embryonic stem cells (ESCs) and somatic cells isolated from bone marrow or spleen and performed a comparative analysis of the electrophysiological properties of tetraploid fusion-derived PSCs and diploid ESC-derived CMs. Fusion-derived PSCs exhibited characteristics of genuine ESCs and contained a near-tetraploid genome. Ploidy features and marker expression were also retained during the differentiation of fusion-derived cells. Fusion-derived PSCs gave rise to CMs, which were similar to their diploid ESC counterparts in terms of their expression of typical cardiospecific markers, sarcomeric organization, action potential parameters, response to pharmacologic stimulation with various drugs, and expression of functional ion channels. These results suggest that the state of ploidy does not significantly affect the structural and electrophysiological properties of murine PSC-derived CMs. These results extend our knowledge of the functional properties of polyploid CMs and contribute to a better understanding of their biological role in the adult heart.
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Engelmann C, Martino VD, Kerbert AJC, Weil-Verhoeven D, Aehling NF, Herber A, Thévenot T, Berg T. The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure. Semin Liver Dis 2021; 41:298-307. [PMID: 33992029 DOI: 10.1055/s-0041-1723034] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.
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Affiliation(s)
- Cornelius Engelmann
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom.,Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany.,Division of Hepatology and Gastroenterology, Department of Medical, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Vincent Di Martino
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Annarein J C Kerbert
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom
| | - Delphine Weil-Verhoeven
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Niklas Friedemann Aehling
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Adam Herber
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Thierry Thévenot
- Service d'Hépatologie et de Soins Intensifs Digestifs, Hôpital Jean Minjoz, 25000 Besançon, France
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
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Tavares MR, de Castro RVG, Pieri NCG, Cruz NRN, Martins DS, Ambrósio CE, Garcia JM, Camplesi AC, Bressan FF, Toniollo GH. Identification of hepatic progenitor cells in the canine fetal liver. Res Vet Sci 2020; 133:239-245. [PMID: 33032111 DOI: 10.1016/j.rvsc.2020.09.012] [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: 03/10/2020] [Revised: 06/08/2020] [Accepted: 09/14/2020] [Indexed: 10/23/2022]
Abstract
The liver plays essential roles in human and animal organisms, such as the storage, release, metabolism, and elimination of various endogenous or exogenous substances. Although its vital importance, few treatments are yet available when a hepatic failure occurs, and hence, the use of stem cells has arisen as a possible solution for both human and veterinary medicines. Previous studies have shown the existence of hepatic progenitor cells in human fetuses that were positive for EpCAM and NCAM. There is limited evidence, however, further identification and characterization of these cells in other species. Considering the similarity between dogs and humans regarding physiology, and also the increasing importance of developing new treatments for both veterinary and translational medicine, this study attempted to identify hepatic progenitor cells in canine fetal liver. For that, livers from canine fetuses were collected, cells were isolated by enzymatic digestion and cultured. Cells were characterized regarding morphology and expression of EpCAM, NCAM, Nestin, and Thy-1/CD90 markers. Our results suggest that it is possible to identify hepatic progenitor cells in the canine fetal liver; however, for therapeutic use, further techniques for cellular isolation and culture are necessary to obtain enriched populations of hepatic progenitors from the canine fetal liver.
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Affiliation(s)
- M R Tavares
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil.
| | - R V G de Castro
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil; Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil
| | - N C G Pieri
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil
| | - N R N Cruz
- Department of Veterinary Clinical and Surgery, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
| | - D S Martins
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil; Post-Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo/SP, Brazil
| | - C E Ambrósio
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil; Post-Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo/SP, Brazil
| | - J M Garcia
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
| | - A C Camplesi
- Department of Veterinary Clinical and Surgery, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
| | - F F Bressan
- Department of Veterinary Medicine, Faculty of Animal Science and Food Engineering, University of São Paulo, Pirassununga/SP, Brazil; Post-Graduate Program in Anatomy of Domestic and Wild Animals, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, São Paulo/SP, Brazil..
| | - G H Toniollo
- Department of Preventive Veterinary Medicine and Animal Reproduction, Faculty of Agricultural and Animal Science, State University of São Paulo, Jaboticabal/SP, Brazil
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Platelets Boost Recruitment of CD133 + Bone Marrow Stem Cells to Endothelium and the Rodent Liver-The Role of P-Selectin/PSGL-1 Interactions. Int J Mol Sci 2020; 21:ijms21176431. [PMID: 32899390 PMCID: PMC7504029 DOI: 10.3390/ijms21176431] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
We previously demonstrated that clinical administration of mobilized CD133+ bone marrow stem cells (BMSC) accelerates hepatic regeneration. Here, we investigated the potential of platelets to modulate CD133+BMSC homing to hepatic endothelial cells and sequestration to warm ischemic livers. Modulatory effects of platelets on the adhesion of CD133+BMSC to human and mouse liver-sinusoidal- and micro- endothelial cells (EC) respectively were evaluated in in vitro co-culture systems. CD133+BMSC adhesion to all types of EC were increased in the presence of platelets under shear stress. This platelet effect was mostly diminished by antagonization of P-selectin and its ligand P-Selectin-Glyco-Ligand-1 (PSGL-1). Inhibition of PECAM-1 as well as SDF-1 receptor CXCR4 had no such effect. In a model of the isolated reperfused rat liver subsequent to warm ischemia, the co-infusion of platelets augmented CD133+BMSC homing to the injured liver with heightened transmigration towards the extra sinusoidal space when compared to perfusion conditions without platelets. Extravascular co-localization of CD133+BMSC with hepatocytes was confirmed by confocal microscopy. We demonstrated an enhancing effect of platelets on CD133+BMSC homing to and transmigrating along hepatic EC putatively depending on PSGL-1 and P-selectin. Our insights suggest a new mechanism of platelets to augment stem cell dependent hepatic repair.
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Dörnen J, Sieler M, Weiler J, Keil S, Dittmar T. Cell Fusion-Mediated Tissue Regeneration as an Inducer of Polyploidy and Aneuploidy. Int J Mol Sci 2020; 21:E1811. [PMID: 32155721 PMCID: PMC7084716 DOI: 10.3390/ijms21051811] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/28/2020] [Accepted: 03/04/2020] [Indexed: 12/20/2022] Open
Abstract
The biological phenomenon of cell fusion plays a crucial role in several physiological processes, including wound healing and tissue regeneration. Here, it is assumed that bone marrow-derived stem cells (BMSCs) could adopt the specific properties of a different organ by cell fusion, thereby restoring organ function. Cell fusion first results in the production of bi- or multinucleated hybrid cells, which either remain as heterokaryons or undergo ploidy reduction/heterokaryon-to-synkaryon transition (HST), thereby giving rise to mononucleated daughter cells. This process is characterized by a merging of the chromosomes from the previously discrete nuclei and their subsequent random segregation into daughter cells. Due to extra centrosomes concomitant with multipolar spindles, the ploidy reduction/HST could also be associated with chromosome missegregation and, hence, induction of aneuploidy, genomic instability, and even putative chromothripsis. However, while the majority of such hybrids die or become senescent, aneuploidy and genomic instability appear to be tolerated in hepatocytes, possibly for stress-related adaption processes. Likewise, cell fusion-induced aneuploidy and genomic instability could also lead to a malignant conversion of hybrid cells. This can occur during tissue regeneration mediated by BMSC fusion in chronically inflamed tissue, which is a cell fusion-friendly environment, but is also enriched for mutagenic reactive oxygen and nitrogen species.
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Affiliation(s)
| | | | | | | | - Thomas Dittmar
- Institute of Immunology, Center for Biomedical Education and Research (ZBAF), Witten/Herdecke University, 58448 Witten, Germany; (J.D.); (M.S.); (J.W.); (S.K.)
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Sahin C, Mamillapalli R, Taylor HS. Bone Marrow-Derived Cells Trafficking to the Oviduct: Effect of Ischemia-Reperfusion Injury. Reprod Sci 2018; 25:1037-1044. [PMID: 29658434 DOI: 10.1177/1933719118770552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The oviduct/fallopian tube is a crucial organ in the mammalian reproductive tract; it plays a critical role in gamete transportation and early embryo development. In women, torsion of the fallopian tubes can cause ischemia and reperfusion (IR) injury. In this study, we tested the effect of this injury on recruitment of bone marrow-derived cells (BMDCs) to the oviducts of reproductive age female mice. Bone marrow-derived cells were collected from ubiquitin-green fluorescent protein-positive male mice and transplanted into wild-type female mice. Ischemia and reperfusion injury was performed in half of the mice, while controls received equivalent surgery without oviduct injury. Two weeks following injury, recruitment of BMDCs to the oviducts was analyzed in both groups. Ischemia and reperfusion injury caused a greater than 2-fold increase in BMDC recruitment to the injured oviducts compared to those without injury. Specifically, the recruitment of BMDCs was localized to the stroma of the oviduct. We demonstrate that IR injury to oviduct recruits BMDCs to this tissue and suggest that BMDCs have function in the healing process.
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Affiliation(s)
- Cagdas Sahin
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Ramanaiah Mamillapalli
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
| | - Hugh S Taylor
- 1 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA
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9
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Allen KJ, Cheah DMY, Lee XL, Pettigrew-Buck NE, Vadolas J, Mercer JFB, Ioannou PA, Williamson R. The Potential of Bone Marrow Stem Cells to Correct Liver Dysfunction in a Mouse Model of Wilson's Disease. Cell Transplant 2017; 13:765-73. [PMID: 15690978 DOI: 10.3727/000000004783983341] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Metabolic liver diseases are excellent targets for correction using novel stem cell, hepatocyte, and gene therapies. In this study, the use of bone marrow stem cell transplantation to correct liver disease in the toxic milk (tx) mouse, a murine model for Wilson's disease, was evaluated. Preconditioning with sublethal irradiation, dietary copper loading, and the influence of cell transplantation sites were assessed. Recipient tx mice were sublethally irradiated (4 Gy) prior to transplantation with bone marrow stem cells harvested from normal congenic (DL) littermates. Of 46 transplanted tx mice, 11 demonstrated genotypic repopulation in the liver. Sublethal irradiation was found to be essential for donor cell engraftment and liver repopulation. Dietary copper loading did not improve cell engraftment and repopulation results. Both intravenously and intrasplenically transplanted cells produced similar repopulation successes. Direct evidence of functionality and disease correction following liver repopulation was observed in the 11 mice where liver copper levels were significantly reduced when compared with mice with no liver repopulation. The reversal of copper loading with bone marrow cells is similar to the level of correction seen when normal congenic liver cells are used. Transplantation of bone marrow cells partially corrects the metabolic phenotype in a mouse model for Wilson's disease.
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Affiliation(s)
- Katrina J Allen
- Cell and Gene Therapy Group, Murdoch Childrens Research Institute, Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
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Vasconcellos R, Alvarenga ÉC, Parreira RC, Lima SS, Resende RR. Exploring the cell signalling in hepatocyte differentiation. Cell Signal 2016; 28:1773-88. [DOI: 10.1016/j.cellsig.2016.08.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/18/2016] [Accepted: 08/18/2016] [Indexed: 02/08/2023]
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Cai Y, Ying F, Song E, Wang Y, Xu A, Vanhoutte PM, Tang EHC. Mice lacking prostaglandin E receptor subtype 4 manifest disrupted lipid metabolism attributable to impaired triglyceride clearance. FASEB J 2015; 29:4924-36. [PMID: 26271253 DOI: 10.1096/fj.15-274597] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 08/03/2015] [Indexed: 12/13/2022]
Abstract
Upon high-fat feeding, prostaglandin E receptor subtype 4 (EP4)-knockout mice gain less body weight than their EP4(+/+) littermates. We investigated the cause of the lean phenotype. The mice showed a 68.8% reduction in weight gain with diminished fat mass that was not attributable to reduced food intake, fat malabsorption, or increased energy expenditure. Plasma triglycerides in the mice were elevated by 244.9%. The increase in plasma triglycerides was independent of changes in hepatic very low density lipoprotein (VLDL)-triglyceride production or intestinal chylomicron-triglyceride synthesis. However, VLDL-triglyceride clearance was drastically impaired in the EP4-knockout mice. The absence of EP4 in mice compromised the activation of lipoprotein lipase (LPL), the key enzyme responsible for trafficking of plasma triglycerides into peripheral tissues. Deficiency in EP4 reduced hepatic mRNA expression of the transcriptional factor cAMP response element binding protein H (by 36.8%) and LPL activators, including apolipoprotein (Apo)a5 (by 40.2%) and Apoc2 (by 61.3%). In summary, the lean phenotype of EP4-deficient mice resulted from reduction in adipose tissue and accretion of other peripheral organs caused by impaired triglyceride clearance. The findings identify a new metabolic dimension in the physiologic role played by endogenous EP4.
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Affiliation(s)
- Yin Cai
- *Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Fan Ying
- *Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Erfei Song
- *Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Yu Wang
- *Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- *Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Paul M Vanhoutte
- *Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Eva Hoi-Ching Tang
- *Department of Pharmacology and Pharmacy, Department of Medicine, Department of Physiology, and the State Key Laboratory of Pharmaceutical Biotechnology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Alejandra MR, Juan AB, Ana SR. Cell therapy for liver diseases: current medicine and future promises. Expert Rev Gastroenterol Hepatol 2015; 9:837-50. [PMID: 25747732 DOI: 10.1586/17474124.2015.1016913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Liver diseases are a major health problem worldwide since they usually represent the main causes of death in most countries, causing excessive costs to public health systems. Nowadays, there are no efficient current therapies for most hepatic diseases and liver transplant is infrequent due to the availability of organs, cost and risk of transplant rejection. Therefore, alternative therapies for liver diseases have been developed, including cell-based therapies. Stem cells (SCs) are characterized by their self-renewing capacity, unlimited proliferation and differentiation under certain conditions into tissue- or organ-specific cells with special functions. Cell-based therapies for liver diseases have been successful in experimental models, showing anti-inflammatory, antifibrogenic and regenerative effects. Nowadays, clinical trials using SCs for liver pathologies are increasing in number, and those that have reached publication have achieved favorable effects, encouraging us to think that SCs will have a potential clinical use in a short time.
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Affiliation(s)
- Meza-Ríos Alejandra
- Department of Molecular Biology and Genomics, Health Sciences University Center, Institute for Molecular Biology and Gene Therapy, University of Guadalajara, Sierra Mojada 950, Colonia Independencia, Guadalajara, Jalisco 44340, México
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13
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Parris GE. Cell-Cell Fusion, Chemotaxis and Metastasis. INTERCELLULAR COMMUNICATION IN CANCER 2015:227-254. [DOI: 10.1007/978-94-017-7380-5_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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14
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Patil PB, Begum S, Joshi M, Kleman MI, Olausson M, Sumitran-Holgersson S. Phenotypic and in vivo functional characterization of immortalized human fetal liver cells. Scand J Gastroenterol 2014; 49:705-14. [PMID: 24730442 PMCID: PMC4059185 DOI: 10.3109/00365521.2013.830328] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We report the establishment and characterization of immortalized human fetal liver progenitor cells by expression of the Simian virus 40 large T (SV40 LT) antigen. Well-characterized cells at various passages were transplanted into nude mice with acute liver injury and tested for functional capacity. The SV40LT antigen-immortalized fetal liver cells showed a morphology similar to primary cells. Cultured cells demonstrated stable phenotypic expression in various passages, of hepatic markers such as albumin, CK 8, CK18, transcription factors HNF-4α and HNF-1α and CYP3A/7. The cells did not stain for any of the tested cancer-associated markers. Albumin, HNF-4α and CYP3A7 expression was confirmed by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry showed expression of some progenitor cell markers. In vivo study showed that the cells expressed both fetal and differentiated hepatocytes markers. Our study suggests new approaches to expand hepatic progenitor cells, analyze their fate in animal models aiming at cell therapy of hepatic diseases.
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Affiliation(s)
- Pradeep B. Patil
- Laboratory of Transplantation and Regenerative Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden,Correspondence: Professor, Suchitra Sumitran-Holgersson, Laboratory of Transplantation Surgery and Regenerative Medicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska Science Park, Medicinaregatan 8A, S-413 46 Gothenburg, Sweden. +46 0 31 3432100.
| | - Setara Begum
- Laboratory of Transplantation and Regenerative Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden,Correspondence: Professor, Suchitra Sumitran-Holgersson, Laboratory of Transplantation Surgery and Regenerative Medicine, Sahlgrenska Academy at University of Gothenburg, Sahlgrenska Science Park, Medicinaregatan 8A, S-413 46 Gothenburg, Sweden. +46 0 31 3432100.
| | - Meghnad Joshi
- Laboratory of Transplantation and Regenerative Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | | | - Michael Olausson
- Laboratory of Transplantation and Regenerative Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
| | - Suchitra Sumitran-Holgersson
- Laboratory of Transplantation and Regenerative Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
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Stock P, Brückner S, Winkler S, Dollinger MM, Christ B. Human bone marrow mesenchymal stem cell-derived hepatocytes improve the mouse liver after acute acetaminophen intoxication by preventing progress of injury. Int J Mol Sci 2014; 15:7004-28. [PMID: 24758938 PMCID: PMC4013675 DOI: 10.3390/ijms15047004] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 04/02/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells from human bone marrow (hMSC) have the potential to differentiate into hepatocyte-like cells in vitro and continue to maintain important hepatocyte functions in vivo after transplantation into host mouse livers. Here, hMSC were differentiated into hepatocyte-like cells in vitro (hMSC-HC) and transplanted into livers of immunodeficient Pfp/Rag2⁻/⁻ mice treated with a sublethal dose of acetaminophen (APAP) to induce acute liver injury. APAP induced a time- and dose-dependent damage of perivenous areas of the liver lobule. Serum levels of aspartate aminotransferase (AST) increased to similar levels irrespective of hMSC-HC transplantation. Yet, hMSC-HC resided in the damaged perivenous areas of the liver lobules short-term preventing apoptosis and thus progress of organ destruction. Disturbance of metabolic protein expression was lower in the livers receiving hMSC-HC. Seven weeks after APAP treatment, hepatic injury had completely recovered in groups both with and without hMSC-HC. Clusters of transplanted cells appeared predominantly in the periportal portion of the liver lobule and secreted human albumin featuring a prominent quality of differentiated hepatocytes. Thus, hMSC-HC attenuated the inflammatory response and supported liver regeneration after acute injury induced by acetaminophen. They hence may serve as a novel source of hepatocyte-like cells suitable for cell therapy of acute liver diseases.
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Affiliation(s)
- Peggy Stock
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany.
| | - Sandra Brückner
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany.
| | - Sandra Winkler
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany.
| | - Matthias M Dollinger
- Clinics for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, D-89081 Ulm, Germany.
| | - Bruno Christ
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Applied Molecular Hepatology Laboratory, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig, Germany.
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Lehwald N, Duhme C, Wildner M, Kuhn S, Fürst G, Forbes SJ, Jonas S, Robson SC, Knoefel WT, Schmelzle M, Schulte Am Esch J. HGF and SDF-1-mediated mobilization of CD133+ BMSC for hepatic regeneration following extensive liver resection. Liver Int 2014; 34:89-101. [PMID: 23701640 DOI: 10.1111/liv.12195] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Accepted: 04/04/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND The molecular mechanisms of haematopoietic stem cells (HSC) mobilization and homing to the liver after partial hepatectomy (PH) remain largely unexplored. METHODS Functional liver volume loss and regain was determined by computerized tomography (CT) volumetry in 30 patients following PH. Peripheral HSC mobilization was investigated by fluorescence-activated cell sorting (FACS) analyses and cytokine enzyme-linked immunosorbent assay assays. Migration of purified HSC towards hepatic growth factor (HGF) and stroma-derived factor-1 (SDF-1) gradients was tested in vitro. Mice after 70% PH were examined for HSC mobilization by FACS and cytokine mRNA expression in the liver. FACS-sorted HSC were administered after PH and hepatocyte proliferation was evaluated by immunohistochemical staining for Ki67. RESULTS Impaired liver function was noted after extended hepatic resection when compared to smaller resections. Patients with large liver resections were characterized by significantly higher levels of peripheral HSC which were positively correlated with the extent of resected liver volume and its regain after 3 weeks. Increased plasma levels of HGF, SDF-1 and insulin like growth factor (IGF-1) were evident within the first 6 hours post resection. Migration assays of human HSC in vitro showed a specific target-demonstrated migration towards recombinant HGF and SDF-1 gradients in a concentration and specific receptor (c-Met and CXCR4) dependent manner. The evaluation of peripheral human alpha foetoprotein expression demonstrated pronounced stemness following increased CD133(+) HSC in the course of liver regeneration following PH. Our human data were further validated in a murine model of PH and furthermore demonstrated increased hepatocyte proliferation subsequent to CD133(+) HSC treatment. CONCLUSION HGF and SDF-1 are required for effective HSC mobilization and homing to the liver after hepatic resection. These findings have significant implications for potential therapeutic strategies targeting chemotactant modulation and stem cell mobilization for liver protection and regeneration.
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Affiliation(s)
- Nadja Lehwald
- Department of Surgery, University Hospital Düsseldorf, Düsseldorf, Germany
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17
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Li Z, Chen J, Li L, Ran JH, Liu J, Gao TX, Guo BY, Li XH, Liu ZH, Liu GJ, Gao YC, Zhang XL. In vitro proliferation and differentiation of hepatic oval cells and their potential capacity for intrahepatic transplantation. Braz J Med Biol Res 2013; 46:681-8. [PMID: 23903688 PMCID: PMC3854420 DOI: 10.1590/1414-431x20132620] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 03/25/2013] [Indexed: 01/28/2023] Open
Abstract
Hepatic oval cells (HOCs) are recognized as facultative liver progenitor cells that
play a role in liver regeneration after acute liver injury. Here, we investigated the
in vitro proliferation and differentiation characteristics of
HOCs in order to explore their potential capacity for intrahepatic transplantation.
Clusters or scattered HOCs were detected in the portal area and interlobular bile
duct in the liver of rats subjected to the modified 2-acetylaminofluorene and partial
hepatectomy method. Isolated HOCs were positive for c-kit and CD90 staining (99.8%
and 88.8%, respectively), and negative for CD34 staining (3.6%) as shown by
immunostaining and flow cytometric analysis. In addition, HOCs could be
differentiated into hepatocytes and bile duct epithelial cells after leukemia
inhibitory factor deprivation. A two-cuff technique was used for orthotopic liver
transplantation, and HOCs were subsequently transplanted into recipients. Biochemical
indicators of liver function were assessed 4 weeks after transplantation. HOC
transplantation significantly prolonged the median survival time and improved the
liver function of rats receiving HOCs compared to controls (P=0.003, Student
t-test). Administration of HOCs to rats also receiving liver
transplantation significantly reduced acute allograft rejection compared to control
liver transplant rats 3 weeks following transplantation (rejection activity index
score: control=6.3±0.9; HOC=3.5±1.5; P=0.005). These results indicate that HOCs may
be useful in therapeutic liver regeneration after orthotopic liver
transplantation.
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Affiliation(s)
- Z Li
- Liaocheng People's Hospital, Department of Hepatobiliary Surgery, LiaochengShandong, China
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Abstract
Reactive stroma initiates during early prostate cancer development and coevolves with prostate cancer progression. Previous studies have defined the key markers of reactive stroma and have established that reactive stroma biology influences prostate tumorigenesis and progression. The stem/progenitor cells of origin and the mechanisms that regulate their recruitment and activation to myofibroblasts or carcinoma-associated fibroblasts are essentially unknown. Key regulatory factors have been identified, including transforming growth factor β, interleukin-8, fibroblast growth factors, connective tissue growth factor, wingless homologs-Wnts, and stromal cell-derived factor-1, among others. The biology of reactive stroma in cancer is similar to the more predictable biology of the stroma compartment during wound repair at sites where the epithelial barrier function is breached and a stromal response is generated. The coevolution of reactive stroma and the biology of how reactive stroma-carcinoma interactions regulate cancer progression and metastasis are targets for new therapeutic approaches. Such approaches are strategically designed to inhibit cancer progression by uncoupling the reactive stroma niche.
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Affiliation(s)
- David A Barron
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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19
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Christ B, Stock P. Mesenchymal stem cell-derived hepatocytes for functional liver replacement. Front Immunol 2012; 3:168. [PMID: 22737154 PMCID: PMC3381218 DOI: 10.3389/fimmu.2012.00168] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 06/04/2012] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells represent an alternate cell source to substitute for primary hepatocytes in hepatocyte transplantation because of their multiple differentiation potential and nearly unlimited availability. They may differentiate into hepatocyte-like cells in vitro and maintain specific hepatocyte functions also after transplantation into the regenerating livers of mice or rats both under injury and non-injury conditions. Depending on the underlying liver disease their mode of action is either to replace the diseased liver tissue or to support liver regeneration through their anti-inflammatory and anti-apoptotic as well as their pro-proliferative action.
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Affiliation(s)
- Bruno Christ
- Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig Leipzig, Germany
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20
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Human unrestricted somatic stem cells: how far from clinics? ASAIO J 2012; 58:181-2. [PMID: 22543753 DOI: 10.1097/mat.0b013e3182545d1d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Bujdosó L, Budán F, Varjas T, Szabó L, Csejtei A, Iványi J, Huszár A, Arany I, Kiss I, Ember I. Herbal compounds increased the level of CD34 positive cells in peripheral blood — An experimental work. ACTA ALIMENTARIA 2012. [DOI: 10.1556/aalim.2011.0001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Infusion of CD133+ bone marrow-derived stem cells after selective portal vein embolization enhances functional hepatic reserves after extended right hepatectomy: a retrospective single-center study. Ann Surg 2012; 255:79-85. [PMID: 22156926 DOI: 10.1097/sla.0b013e31823d7d08] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE This study was designed to evaluate the clinical outcome of patients undergoing portal vein embolization (PVE) and autologous CD133 bone marrow-derived stem cell (CD133+ BMSC) application before extended right hepatectomy. BACKGROUND We have previously shown that portal venous infusion of CD133+ BMSCs substantially increases hepatic proliferation, when compared with PVE alone. METHODS : Among 40 consecutive patients with a median follow-up of 28 months (7.4-57.2) scheduled for extended right hepatectomy, we compared a preconditioned group with PVE and CD133+ BMSC cotreatment (PVE+SC group, n = 11) and a group pretreated only with PVE (PVE group, n = 11). Functional and overall outcomes after extended right hepatectomy were evaluated. Patients without presurgical treatment served as controls (n = 18). RESULTS In preconditioned patients, mean hepatic growth of segments II/III 14 days after PVE in the PVE+SC group was significantly higher (138.66 mL ± 66.29) when compared with that of PVE group patients (62.95 mL ± 40.03; P = 0.004). There were no significant differences among all 3 groups regarding general and oncological characteristics and functional parameters on postoperative day (POD) 7. Lack of hepatic preconditioning, extrahepatic extension of resection, and postoperative complications were of negative prognostic value, using univariate analysis (P < 0.05). In multivariate analysis, freedom from postoperative major complications (P = 0.012), coagulation status on POD 7 (international normalized ratio < 1.4; P = 0.027), and presurgical expansion of the future liver remnant volume (P = 0.048) were positively associated with overall survival. Post hoc analysis revealed a better survival for the PVE+SC group (P = 0.028) compared with the PVE group (P = 0.094) and compared with controls. CONCLUSION Promising data from this survival analysis suggest that PVE, together with CD133+ BMSC pretreatment, could positively impact overall outcomes after extended right hepatectomy.
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23
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Krishna KA, Krishna KS, Berrocal R, Tummala A, Rao K, Rao KS. A review on the therapeutic potential of embryonic and induced pluripotent stem cells in hepatic repair. J Nat Sci Biol Med 2011; 2:141-4. [PMID: 22346225 PMCID: PMC3276003 DOI: 10.4103/0976-9668.92314] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Despite the liver being proliferatively quiescent, it maintains balance between cell gain and cell loss, invokes a rapid regenerative response following hepatocyte loss, and restores liver mass. Human liver has immense regenerative capacity. Liver comprises many cell types with specialized functions. Of these cell types, hepatocytes play several key roles, but are most vulnerable to damage. Recent studies suggest that the extrahepatic stem cell pool contributes to liver regeneration. Stem cell therapies have the potential to enhance hepatic regeneration. Both embryonic and induced pluripotent stem cells could be a suitable source to regenerate hepatocytes. In the present review, we discuss the therapeutic potential of stem cells in hepatic repair and focus on the clinical applications of stem cells.
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Affiliation(s)
- K. Ananda Krishna
- Department of Biotechnology, Acharya Nagarjuna University, Guntur, India
| | - K. Sai Krishna
- Department of Biotechnology, Meenakshi Medical College and Research Institute, Enathur, Kancheepuram, Tamilnadu, India
| | - Ruben Berrocal
- Institute for Scientific Research and Technology Services, National Secretariat for Science, Technology and Innovation, Clayton City of Knowledge, Republic of Panama
| | - Alekya Tummala
- Department of Clinical Biochemistry, Columbus College of Medicine, Republic of Panama
| | - K.S. Rao
- Institute for Scientific Research and Technology Services, National Secretariat for Science, Technology and Innovation, Clayton City of Knowledge, Republic of Panama
| | - K.R.S. Sambasiva Rao
- Department of Biotechnology, Acharya Nagarjuna University, Guntur, India
- Institute for Scientific Research and Technology Services, National Secretariat for Science, Technology and Innovation, Clayton City of Knowledge, Republic of Panama
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Jin SZ, Meng XW, Sun X, Han MZ, Liu BR, Wang XH, Sun LY, Huang Q, Zhao RB, Ban X, Yu HY, Yu HW. Granulocyte colony-stimulating factor enhances bone marrow mononuclear cell homing to the liver in a mouse model of acute hepatic injury. Dig Dis Sci 2010; 55:2805-13. [PMID: 20130994 DOI: 10.1007/s10620-009-1117-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Accepted: 12/28/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND Experiments have reported that granulocyte colony stimulating factor (G-CSF) can mobilize stem cells. However, few studies have examined the effect of G-CSF on bone marrow mononuclear cell (BMMC) mobilization, in particular regarding their capability to home to acutely injured liver. AIMS The aim of this study was to evaluate the effort of G-CSF on BMMC homing to the liver following chemically-induced hepatic failure. METHODS BMMC were isolated from mice, pre-labeled with PKH26 and infused into the mice in which hepatic injury had been induced followed by administration of G-CSF or vehicle. Livers were studied by fluorescent microscopy after transplantation of pre-labeled BMMC. RESULTS PKH26 labeled cells were found in liver tissue at 102 ± 10 cells/high power field in the BMMC+G-CSF group and 30 ± 5 cells/high power field in the BMMC group, but none in the G-CSF group and the control group (P < 0.05). In the former two groups the majority of PKH26 labeled cells colocalized with proliferative cell nuclear antigen (PCNA). The number of PCNA positive cells in the BMMC+G-CSF group was 20 ± 4 cells/high power field, while in the BMMC group it was 14 ± 2 cells/high power field, in the G-CSF group 12 ± 2 cells/high power field, and 8 ± 1 cells/high power field in the control group. Moreover, albumin expression was increased in the BMMC+G-CSF treated group (149 ± 7/high power field) relative to the BMMC group (48 ± 6/high power field), the G-CSF group (44 ± 5/high power field) and the vehicle group (30 ± 6/high power field), with the former three groups showing elevated levels as compared to vehicle control (30 ± 6) (P < 0.05). CONCLUSION Transplanted BMMC may home to injured liver, which appears to be enhanced by G-CSF administration.
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Affiliation(s)
- Shi-Zhu Jin
- Department of Gastroenterology, First Hospital, Jilin University, 130021, Changchun, China
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25
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Li J, Tao R, Wu W, Cao H, Xin J, Guo J, Jiang L, Hong X, Demetriou AA, Farkas D, Li L. Transcriptional profiling and hepatogenic potential of acute hepatic failure-derived bone marrow mesenchymal stem cells. Differentiation 2010; 80:166-174. [PMID: 20427118 DOI: 10.1016/j.diff.2010.04.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2010] [Revised: 03/17/2010] [Accepted: 04/08/2010] [Indexed: 01/14/2023]
Abstract
UNLABELLED Liver stem cell (LSC) transplantation is a promising alternate approach to liver transplantation for patients with end-stage liver disease. However, the precise origin of LSCs remains unclear. Herein we determine if bone marrow mesenchymal stem cells (BMSCs) isolated from rats in acute hepatic failure (AHF) possess hepatic characteristics and have differentiation potential. BMSCs were isolated from AHF and sham-operated rats, and primary hepatocytes were isolated from normal rats for comparison. The transcriptomic profile of BMSCs and primary hepatocytes was analyzed using the Affymetrix GeneChip Rat Genome 230 2.0 Array. BMSCs isolated from AHF and normal rats were induced to differentiate into hepatocytes in vitro and the degree of hepatic differentiation was assessed using quantitative real time RT-PCR, immunohistochemistry, and biochemical assays. AHF-derived BMSCs had a significantly different gene expression profile compared to control BMSCs. Thirty-four gene/probe sets were expressed in both AHF-derived BMSCs and primary hepatocytes, but were absent in control-derived BMSCs, including 3 hepatocyte-specific genes. Forty-four genes were up-regulated more than 2-fold in AHF-derived BMSCs compared to controls, including 3 genes involved in hepatocyte metabolism and development. Furthermore, AHF-derived BMSCs expressed more hepatocyte related genes than control BMSCs. Additional experiments to validate the differentiation of AHF-derived BMSCs, compared to control-derived BMSCs, showed that several hepatocyte-specific genes and proteins [such as albumin (ALB) and alpha fetoprotein (AFP)] were expressed earlier, and at higher levels, after 1 week of differentiation. Hepatocyte-specific metabolic functions were also significantly higher in the AHF group compared to control cells. CONCLUSION AHF-derived BMSCs had a hepatic transcriptional profile and expressed hepatocyte specific genes early during differentiation, and possessed greater hepatogenic potency in vitro compared to cells isolated from control animals, further confirming their potential as a stem cell-based therapy for end-stage liver disease.
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Affiliation(s)
- Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Rd., Hangzhou 310003, China
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Superti-Furga A, Garavelli L. Current themes in molecular pediatrics: molecular medicine and its applications. Ital J Pediatr 2010; 36:20. [PMID: 20170480 PMCID: PMC2844384 DOI: 10.1186/1824-7288-36-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2010] [Accepted: 02/19/2010] [Indexed: 11/28/2022] Open
Abstract
We focus on themes that are derived from clinical practice and research in the field of genetic diseases of bone and inborn errors of metabolism but may be of more general interest as they indicate some trends in molecular medicine as related to pediatrics. Identifying the disease-causing mechanism brings about efficient therapeutic strategies and discovering the mutant genotype in the near future may become helpful for devising custom-built molecular responses. At the same time, the transition of therapy from the experimental phase to industrial application is difficult as there may be novel roles (and potentially conflicting interests) between physicians, patient organisations, governmental agencies and the pharmaceutical industry. Awareness of these potential conflicts may help in recognizing and dealing with these issues.
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Affiliation(s)
- Andrea Superti-Furga
- Centre for Pediatrics and Adolescent Medicine, University of Freiburg, Freiburg, Germany.
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Dezso K, Paku S, Papp V, Turányi E, Nagy P. Architectural and immunohistochemical characterization of biliary ductules in normal human liver. Stem Cells Dev 2010; 18:1417-22. [PMID: 19552603 DOI: 10.1089/scd.2009.0110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The canals of Hering or biliary ductules have been described to connect the bile canaliculi with the interlobular bile ducts, and thus forming the distal part of the biliary tree. Studies in the last two decades suggested that the cells constructing these ductules could behave as hepatic progenitor cells. The canals of Hering are confined to the periportal space in the rat, while they have been reported to spread beyond the limiting plate in human liver. The distribution of the distal biliary ductules in normal human hepatic tissue has been investigated in our recent experiments. We could demonstrate the presence of interlobular connective tissue septa in a rudimentary form in healthy livers. The canals of Hering run in these septa in line with the terminal branches of the portal vein and hepatic arteries. This arrangement develops in the postnatal period but regresses after early childhood. The canals of Hering can be identified by the unique epithelial membrane antigen (EMA)-/CD56+/CD133+ immunophenotype. The canals of Hering leave the periportal space and spread into the liver parenchyma along rudimentary interlobular septa outlining the hepatic lobules. Our observations refine the original architectural description of the intraparenchymal portion of the canals of Hering in the human liver. The distinct immunophenotype supports their unique biological function.
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Affiliation(s)
- Katalin Dezso
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest 1085, Hungary
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Dollé L, Best J, Mei J, Al Battah F, Reynaert H, van Grunsven LA, Geerts A. The quest for liver progenitor cells: a practical point of view. J Hepatol 2010; 52:117-29. [PMID: 19913937 DOI: 10.1016/j.jhep.2009.10.009] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Many chronic liver diseases can lead to hepatic dysfunction with organ failure. At present, orthotopic liver transplantation represents the benchmark therapy of terminal liver disease. However this practice is limited by shortage of donor grafts, the need for lifelong immunosuppression and very demanding state-of-the-art surgery. For this reason, new therapies have been developed to restore liver function, primarily in the form of hepatocyte transplantation and artificial liver support devices. While already offered in very specialized centers, both of these modalities still remain experimental. Recently, liver progenitor cells have shown great promise for cell therapy, and consequently they have attracted a lot of attention as an alternative or supportive tool for liver transplantation. These liver progenitor cells are quiescent in the healthy liver and become activated in certain liver diseases in which the regenerative capacity of mature hepatocytes and/or cholangiocytes is impaired. Although reports describing liver progenitor cells are numerous, they have not led to a consensus on the identity of the liver progenitor cell. In this review, we will discuss some of the characteristics of these cells and the different ways that have been used to obtain these from rodents. We will also highlight the challenges that researchers are facing in their quest to identify and use liver progenitor cells.
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Affiliation(s)
- Laurent Dollé
- Department of Cell Biology, Vrije Universiteit Brussel, Belgium
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29
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Satoh A, Saito T, Sato Y, Tsuchiya T, Kenjo A, Kimura T, Kanno R, Suzuki H, Kogure M, Hoshino Y, Gotoh M. Traffic of infused bone marrow cells after genetically-labeled syngeneic bone marrow transplantation following lethal irradiation in mice. Fukushima J Med Sci 2008; 54:11-24. [PMID: 18924549 DOI: 10.5387/fms.54.11] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
UNLABELLED Bone marrow (BM) cells are considered the source of stem cells for various organs. However, how quickly BM cells can penetrate and constitute lymphoid organs remains elusive. In the present study, we addressed this issue in a model using genetically-labeled syngeneic BM transplantation (BMT). METHODS Donor BM cells were obtained from "green mice", transgenic mice with enhanced GFP. Lethally irradiated C57BL/6 mice were infused with 1 x 10(6) BM cells from the green mice through the tail vein. BM chimerism was analyzed by FACS and the presence of donor BM cells in thoracoabdominal organs was assessed by fluorescence microscopy. The commitment of BM cells was examined by immunohistochemical staining using epithelium-, macrophage-, B and T-lymphocyte, and endothelium-specific antibodies. RESULTS BM chimerism reached 40+/- 18.5%, 82.6 +/- 23.4%, and 72 +/- 18% (mean +/- SD) at 1, 4, and 12 wks after BMT, respectively. GFP-positive cells were detected in all organs in the course of chimeric formation. Most GFP-positive cells were T and B lymphocytes in lymphoid systems including spleen, thymus, mesenteric lymph nodes and microvilli, and some were positive for macrophage and endothelial cell markers. CONCLUSIONS Our results indicate that BM-derived cells migrate rapidly into various thoracoabdominal organs after BMT, and that lymphoid tissues are predominantly replaced with infused BM in lethally-irradiated mice. This confirmed the previous finding by others and suggests high interest of this model for further studies to characterize kinetics and roles of infused cells.
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Affiliation(s)
- Atai Satoh
- Department of Surgery I, Fukushima Medical University, School of Medicine, Fukushima 960-1295, Japan
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Menegazzo M, Bagatella P, Marson P, Donadel C, De Silvestro G, Corsini A. Reduced mobilisation of hematopoietic stem cells after hepatic resection for malignant liver disease. Pathol Oncol Res 2008; 14:381-5. [PMID: 18752047 DOI: 10.1007/s12253-008-9091-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Accepted: 07/28/2008] [Indexed: 10/21/2022]
Abstract
Recent studies have demonstrated that hematopoietic stem cells (HSCs) can mobilize following liver resection, thus contributing to the repair of hepatic damage. Aim of this study has been to determine whether the nature of the hepatic lesion (benign vs. malignant disease) can give rise to a different degree of mobilisation of HSCs. Two groups of patients were selected: the first included seven patients undergoing hepatic resection (five major and two minor) for a benign liver disease (focal nodular hyperplasia, hemangioma cavernosa, angioma, biliary adenofibroma) and the second included seven patients undergoing hepatic resection (five major and two minor) for a malignant (either primary or secondary) liver disease. White blood cell count and CD34+ (percentage and total number) at time T(0) (basal value before surgery) and at time T(1) (value on the sixth-eighth day after surgery) have been evaluated by standard methods. In the group undergoing hepatic resection for a benign liver disease, a significant increase of CD34+ cells, both in percentage (0.082 +/- 0.043 vs. 0.048 +/- 0,026, p = 0.041) and in absolute number (8.14 +/- 5.95 vs. 3.26 +/- 2.63, p = 0.018) have been documented, as opposed to the group of patients affected with a malignant liver disease, where no significant variation has been observed (CD34+ %: 0.044 +/- 0.033 vs. 0.041 +/- 0.031, p: n.s.; CD34+ total number: 3.52 +/- 2.56 vs. 2.27 +/- 2.01, p = n.s.) These results show a different bone marrow response to the surgical liver resection depending on the nature of the lesion, thus emphasizing a reduced mobilisation of HSCs in the malignant diseases. Since it has been documented that the type of the hepatic lesion can induce a different regenerative response, it has to be explained how the neoplastic lesions can negatively influence the mobilization of HSCs. It can be hypothesized that a variety of humoral factors, including stromal cell-derived factor, matrix metalloproteinases, hepatocyte growth factor and interleukin-8 can influence the process of mobilization of HSCs after liver resection surgery. These substances are also involved in the mechanisms of development and metastasising of many tumours. It is probably in this context that a reason may be found for the different mobilisation of hematopoietic stem cells, depending on the nature of the hepatic lesion treated, that was encountered in this study.
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Rovó A, Gratwohl A. Plasticity after allogeneic hematopoietic stem cell transplantation. Biol Chem 2008; 389:825-836. [DOI: 10.1515/bc.2008.103] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Abstract
The postulated almost unlimited potential of transplanted hematopoietic stem cells (HSCs) to transdifferentiate into cell types that do not belong to the hematopoietic system denotes a complete paradigm shift of the hierarchical hemopoietic tree. In several studies during the last few years, donor cells have been identified in almost all recipient tissues after allogeneic HSC transplantation (HSCT), supporting the theory that any failing organ could be accessible to regenerative cell therapy. However, the putative potential ability of the stem cells to cross beyond lineage barriers has been questioned by other studies which suggest that hematopoietic cells might fuse with non-hematopoietic cells and mimic the appearance of transdifferentiation. Proof that HSCs have preserved the capacity to transdifferentiate into other cell types remains to be demonstrated. In this review, we focus mainly on clinical studies addressing plasticity in humans who underwent allogeneic HSCT. We summarize the published data on non-hematopoietic chimerism, donor cell contribution to tissue repair, the controversies related to the methods used to detect donor-derived non-hematopoietic cells and the functional impact of this phenomenon in diverse specific target tissues and organs.
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Affiliation(s)
- Alicia Rovó
- Hematology Department, University Hospital of Basel, CH-4031 Basel, Switzerland
| | - Alois Gratwohl
- Hematology Department, University Hospital of Basel, CH-4031 Basel, Switzerland
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Fernandes KJ, Toma JG, Miller FD. Multipotent skin-derived precursors: adult neural crest-related precursors with therapeutic potential. Philos Trans R Soc Lond B Biol Sci 2008; 363:185-98. [PMID: 17282990 PMCID: PMC2605494 DOI: 10.1098/rstb.2006.2020] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
We previously made the surprising finding that cultures of multipotent precursors can be grown from the dermis of neonatal and adult mammalian skin. These skin-derived precursors (SKPs) display multi-lineage differentiation potential, producing both neural and mesodermal progeny in vitro, and are an apparently novel precursor cell type that is distinct from other known precursors within the skin. In this review, we begin by placing these findings within the context of the rapidly evolving stem cell field. We then describe our recent efforts focused on understanding the developmental biology of SKPs, discussing the idea that SKPs are neural crest-related precursors that (i) migrate into the skin during embryogenesis, (ii) persist within a specific dermal niche, and (iii) play a key role in the normal physiology, and potentially pathology, of the skin. We conclude by highlighting some of the therapeutic implications and unresolved questions raised by these studies.
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Affiliation(s)
- Karl J.L Fernandes
- Programs in Developmental Biology, University of TorontoToronto, Ontario, Canada M5G 1X8
- Programs in Cancer Research, University of TorontoToronto, Canada M5G 1X8
| | - Jean G Toma
- Programs in Developmental Biology, University of TorontoToronto, Ontario, Canada M5G 1X8
| | - Freda D Miller
- Programs in Developmental Biology, University of TorontoToronto, Ontario, Canada M5G 1X8
- Programs in Brain and Behaviour, University of TorontoToronto, Canada M5G 1X8
- Department of Molecular and Medical Genetics, University of TorontoToronto, Canada M5G 1X8
- Department of Physiology, University of TorontoToronto, Canada M5G 1X8
- Author for correspondence ()
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Swenson ES, Kuwahara R, Krause DS, Theise ND. Physiological variations of stem cell factor and stromal-derived factor-1 in murine models of liver injury and regeneration. Liver Int 2008; 28:308-18. [PMID: 18290773 PMCID: PMC2846401 DOI: 10.1111/j.1478-3231.2007.01659.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS Stem cell factor (SCF) and stromal-derived factor-1 (SDF-1) regulate the regenerative response to liver injury, possibly through activation of liver progenitor 'oval' cells and recruitment of circulating, marrow-derived progenitors. METHODS We performed a detailed analysis of SCF, SDF-1 and oval cell proliferation induced by tyrosinaemia, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or liver irradiation in mice by ELISA and immunofluorescence. RESULTS Liver injury in the tyrosinaemia mouse is characterized by a dramatic decline in plasma SCF and absence of oval cell proliferation. In contrast, DDC induces bile duct (BD) and oval cell proliferation, and a modest decline in plasma SCF. Focal liver irradiation increases plasma SCF, but not oval cell density. In normal mouse liver, SCF is localized primarily to Kupffer cells, cholangiocytes and arterial smooth muscle, with little or no expression in hepatocytes. However, SCF appears in hepatocyte nuclei after injury, where its function is unknown. In all three models, SDF-1 is expressed exclusively in BD epithelium, indicating that tissue SDF-1 levels are proportional to the total mass of oval cells and cholangiocytes. However, increased plasma levels of SDF-1 in fumaryl acetoacetate hydroxylase-null mice were not accompanied by oval cell proliferation. CONCLUSION Changes in SCF and SDF-1 varied with the nature of liver injury and were not directly related to oval cell proliferation.
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Affiliation(s)
- E. Scott Swenson
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Reiichiro Kuwahara
- Liver & Stem Cell Research Laboratory, Department of Medicine, Division of Digestive Diseases, Beth Israel Medical Center, New York, NY, USA
| | - Diane S. Krause
- Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Neil D. Theise
- Liver & Stem Cell Research Laboratory, Department of Medicine, Division of Digestive Diseases, Beth Israel Medical Center, New York, NY, USA
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Stock P, Staege M, Müller L, Sgodda M, Völker A, Volkmer I, Lützkendorf J, Christ B. Hepatocytes Derived From Adult Stem Cells. Transplant Proc 2008; 40:620-3. [DOI: 10.1016/j.transproceed.2008.01.058] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Correction of copper metabolism is not sustained long term in Wilson's disease mice post bone marrow transplantation. Hepatol Int 2008; 2:72-9. [PMID: 19669281 DOI: 10.1007/s12072-007-9039-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2007] [Revised: 09/28/2007] [Accepted: 10/14/2007] [Indexed: 10/22/2022]
Abstract
PURPOSE Alternative cell sources have been sought for the treatment of liver diseases, since liver cells are in short supply for cell transplantation. Although bone marrow-derived cells have been investigated as an alternative cell source, few studies have demonstrated long-term disease correction. Here we examined bone marrow stem cell transplantation into the toxic milk (tx) mouse model for Wilson's disease, a mild liver disease characterized by hepatic copper accumulation. The aim of this study was to determine whether bone marrow cells engrafted in the liver could sustain correction of abnormal copper metabolism in the tx mouse. METHODS Bone marrow cells were isolated from congenic normal mice, transduced to express enhanced green fluorescent protein, sorted for stem cell (Sca-1) and lineage cell (Lin) surface markers, and then transplanted into sub-lethally irradiated normal or tx mice. Analysis for donor cell activity and distribution was undertaken 5 and 9 months post-transplant to allow for sufficient time to repopulate the liver and demonstrate disease correction. RESULTS Donor bone marrow cells engrafted in both normal and tx mouse liver within 5 months. Significantly reduced liver copper was found in tx mice with donor cell liver engraftment at 5 months post-transplant compared to controls, demonstrating partial correction of abnormal copper metabolism in the short term. However, disease correction was not maintained 9 months post-transplantation. Lin(-)Sca-1(+) cells were more likely to partially correct disease than Lin(+)Sca-1(-) cells in the short term. CONCLUSION These results demonstrate that bone marrow transplants cannot maintain disease correction in a mouse model of mild hepatic damage, although initial copper metabolism correction was observed.
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36
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Erker L, Grompe M. Signaling networks in hepatic oval cell activation. Stem Cell Res 2008; 1:90-102. [PMID: 19383389 DOI: 10.1016/j.scr.2008.01.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2007] [Revised: 01/02/2008] [Accepted: 01/12/2008] [Indexed: 12/22/2022] Open
Abstract
Oval cells are hypothesized to be the progeny of intrahepatic stem cells, also referred to as adult liver stem cells. The mechanisms by which these cells are activated to proliferate and differentiate during liver regeneration is important for the development of new therapies to treat liver disease. Oval cell activation is the first step in progenitor-dependent liver regeneration in response to certain types of injury. This review describes what is currently known about the factors involved in oval cell activation, proliferation, migration, and differentiation.
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Affiliation(s)
- Laura Erker
- Oregon Stem Cell Center, Oregon Health Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
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37
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Apte U, Thompson MD, Cui S, Liu B, Cieply B, Monga SPS. Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology 2008; 47:288-95. [PMID: 17929301 DOI: 10.1002/hep.21973] [Citation(s) in RCA: 149] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Adult hepatic stem cells or oval cells are facultative stem cells in the liver that are activated during regeneration only during inhibition of innate hepatocyte proliferation. On the basis of its involvement in liver cancer, regeneration, and development, we investigated the role of the Wnt/beta-catenin pathway in oval cell response, which was initiated in male Fisher rats with 2-acetylaminofluorine and two-third partial hepatectomy (PHX). Extensive oval cell activation and proliferation were observed at 5 and 10 days post-PHX, as indicated by hematoxylin-eosin and proliferating cell nuclear antigen analysis. A noteworthy increase in total and active beta-catenin was observed at this time, which was localized to the oval cell cytoplasm and nuclei by immunohistochemistry and confirmed by double immunofluorescence. A concomitant increase in Wnt-1 in hepatocytes along with increased expression of Frizzled-2 in oval cells was observed. This paracrine mechanism coincided with a decrease in Wnt inhibitory factor-1 and glycogen synthase kinase-3beta down-regulation leading to beta-catenin stabilization. To strengthen its role, beta-catenin conditional knockout mice were treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine to induce oval cell activation. A dramatic decrease in the A6-positive oval cell numbers in the absence of beta-catenin demonstrated a critical role of beta-catenin in oval cell biology. CONCLUSION The Wnt/beta-catenin pathway plays a key role in the normal activation and proliferation of adult hepatic stem cells.
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Affiliation(s)
- Udayan Apte
- Department of Pathology (Cellular and Molecular Pathology), University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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38
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Hines IN, Kremer M, Isayama F, Perry AW, Milton RJ, Black AL, Byrd CL, Wheeler MD. Impaired liver regeneration and increased oval cell numbers following T cell-mediated hepatitis. Hepatology 2007; 46:229-41. [PMID: 17596893 DOI: 10.1002/hep.21674] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
UNLABELLED The regeneration of liver tissue following transplantation is often complicated by inflammation and tissue damage induced by a number of factors, including ischemia and reperfusion injury and immune reactions to the donor tissue. The purpose of the current study is to characterize the effects of T cell-mediated hepatitis induced by concanavalin A (ConA) on the regenerative response in vivo. Liver regeneration following a partial (70%) hepatectomy (pHx) was associated with elevations in serum enzymes and the induction of key cell cycle proteins (cyclin D, cyclin E, and Stat3) and hepatocyte proliferation. The induction of T cell-mediated hepatitis 4 days before pHx increased serum enzymes 48 hours after pHx, reduced early cyclin D expression and Stat3 activation, and suppressed hepatocyte proliferation. This inhibition of proliferation was also associated with increased expression of p21, the activation of Smad2, the induction of transforming growth factor beta and interferon gamma expression, and reduced hepatic interleukin 6 production. Moreover, the ConA pretreatment increased the numbers of separate oval cell-like CD117(+) cells and hematopoietic-like Sca-1(+) cell populations 48 hours following pHx. The depletion of natural killer (NK) cells, an important component of the innate immune response, did not affect liver injury or ConA-induced impairment of hepatocyte proliferation but did increase the numbers of both CD117-positive and Sca-1-positive cell populations. Finally, splenocytes isolated from ConA-pretreated mice exerted cytotoxicity toward autologous bone marrow cells in an NK cell-dependent manner. CONCLUSION T cell-mediated hepatitis alters early cytokine responses, reduces hepatocellular regeneration, and induces NK cell-sensitive oval cell and hematopoietic-like cell expansion following pHx.
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Affiliation(s)
- Ian N Hines
- Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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39
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Immunohistochemical characterization of hepatic stem cell-related cells in developing human liver. ACTA ACUST UNITED AC 2007; 1:264-8. [PMID: 24573863 DOI: 10.1007/s11684-007-0050-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Little is known about the expression characteristics of the various kinds of possible markers in hepatic stem cells (HSCs) and other HSC-related cells in human fetal liver in various developmental stages. It is significant to investigate the immunohistochemical expression for better understanding of the origin, differentiation and migration of HSCs in the developing human liver. H-E staining and immunohistochemical methods were used to observe the expression of hepatic/cholangiocellular differentiation markers (AFP, GST-π, CK7, CK19) and hematopoietic stem cell markers(CD34 and c-kit) in several kinds of HSC-related cells in thirty cases of fetal liver samples (4-35 weeks after pregnancy). AFP expression appears in fetal hepatocytes at four weeks' gestation. It peaks at 16-24 weeks' gestation and decreases gradually afterwards. Finally, weak signals were only found in some ductal plate cells and a few limiting plate cells. GST-π was detected in hepatic cord cells from the sixth week and in the ductal plate cells from the eighth week. Twenty-six weeks later, only some ductal plate cells and a few limiting plate cells show positive signals. CK19 expression peaks during the 6th-11th weeks in hepatic cord cells and decreases gradually afterwards, except for the ductal plates. CK7 expression was limited in the ductal plate cells and bile ducts cells from the 14th week. CD34 and c-kit were detected at the eighth week in some ductal plate cells and a few mononuclear cells in the hepatic cords/mesenchymal tissue of portal areas. After 21 weeks, CD34 and c-kit were found only in ductal plate cells and a few mononuclear cells in the hepatic mesenchymal tissue of portal areas. Fetal hepatocytes at 4-16 weeks' gestation are mainly constituted by HSCs characterized with bi-potential differentiation capacity. At 16 weeks' gestation, most hepatic cord cells begin to differentiate into hepatocytes and abundant HSCs remain in ductal plate (the origin site of Hering canals). It is also indicated that the hematopoietic stem cells may give rise to some HSCs in embryonic liver. These indirectly support the hypothesis about the location and origin of HSCs in "liver valley hypothesis" reported previously.
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Rountree CB, Barsky L, Ge S, Zhu J, Senadheera S, Crooks GM. A CD133-expressing murine liver oval cell population with bilineage potential. Stem Cells 2007; 25:2419-29. [PMID: 17585168 DOI: 10.1634/stemcells.2007-0176] [Citation(s) in RCA: 119] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Although oval cells are postulated to be adult liver stem cells, a well-defined phenotype of a bipotent liver stem cell remains elusive. The heterogeneity of cells within the oval cell fraction has hindered lineage potential studies. Our goal was to identify an enriched population of bipotent oval cells using a combination of flow cytometry and single cell gene expression in conjunction with lineage-specific liver injury models. Expression of cell surface markers on nonparenchymal, nonhematopoietic (CD45-) cells were characterized. Cell populations were isolated by flow cytometry for gene expression studies. 3,5-Diethoxycarbonyl-1,4-dihydrocollidine toxic injury induced cell cycling and expansion specifically in the subpopulation of oval cells in the periportal zone that express CD133. CD133+CD45- cells expressed hepatoblast and stem cell-associated genes, and single cells coexpressed both hepatocyte and cholangiocyte-associated genes, indicating bilineage potential. CD133+CD45- cells proliferated in response to liver injury. Following toxic hepatocyte damage, CD133+CD45- cells demonstrated upregulated expression of the hepatocyte gene Albumin. In contrast, toxic cholangiocyte injury resulted in upregulation of the cholangiocyte gene Ck19. After 21-28 days in culture, CD133+CD45- cells continued to generate cells of both hepatocyte and cholangiocyte lineages. Thus, CD133 expression identifies a population of oval cells in adult murine liver with the gene expression profile and function of primitive, bipotent liver stem cells. In response to lineage-specific injury, these cells demonstrate a lineage-appropriate genetic response. Disclosure of potential conflicts of interest is found at the end of this article.
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Affiliation(s)
- C Bart Rountree
- Division of Gastroenterology, Hepatology, and Nutrition, Childrens Hospital Los Angeles, Los Angeles, California, USA.
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van Poll D, Sokmensuer C, Ahmad N, Tilles AW, Berthiaume F, Toner M, Yarmush ML. Elevated hepatocyte-specific functions in fetal rat hepatocytes co-cultured with adult rat hepatocytes. ACTA ACUST UNITED AC 2007; 12:2965-73. [PMID: 17518664 DOI: 10.1089/ten.2006.12.2965] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Fetal hepatocytes (FHEPs) are a potential source of highly proliferative transplantable cells but express low levels of liver-specific functions. We hypothesized that the microenvironment of adult hepatocytes (AHEPs) may upregulate these functions. Primary FHEPs were seeded on top of collagen-sandwiched AHEPs directly or separated by a porous transwell membrane insert. In direct co-cultures, albumin (ALB) secretion, urea synthesis, and cytochrome P450 (CytP450) activity were all approximately 2 times as high as the sum of the corresponding monocultures. Using a transwell porous insert led to similar results, suggesting a major role for soluble factors. When AHEPs and FHEPs were separated after co-culture, they both initially showed significantly higher ALB secretion than control monocultures, whereas urea synthesis was significantly lower for the FHEPs only. Functions of previously co-cultured FHEPs normalized over the course of a week, but AHEP function remained high even after separation. In conclusion, co-culturing AHEPs with FHEPs increases expression of liver-specific functions in both cell types. The effect on FHEPs, but not AHEPs, was reversible. Unraveling the underlying mechanisms and optimizing this phenomenon will be useful in making fetal liver cells a potential cell source for hepatic tissue-engineering applications.
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Affiliation(s)
- Daan van Poll
- Center for Engineering in Medicine/Surgical Services, Massachusetts General Hospital, Harvard Medical School, and Shriners Burns Hospital, Boston, Massachusetts 02114, USA
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Sobaniec-Lotowska MESL, Lotowska JM, Lebensztejn DM. Ultrastructure of oval cells in children with chronic hepatitis B, with special emphasis on the stage of liver fibrosis: The first pediatric study. World J Gastroenterol 2007; 13:2918-22. [PMID: 17589940 PMCID: PMC4171142 DOI: 10.3748/wjg.v13.i21.2918] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [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 ultrastructure of oval cells in children with chronic hepatitis B, with special emphasis on their location in areas of collagen fibroplasia.
METHODS: Morphological investigations were conducted on biopsy material obtained from 40 children, aged 3-16 years with chronic hepatitis B. The stage of fibrosis was assessed histologically using the arbitrary semiquantitative numerical scoring system proposed by Ishak et al. The material for ultrastructural investigation was fixed in glutaraldehyde and paraformaldehyde and processed for transmission–electron microscopic analysis.
RESULTS: Ultrastructural examination of biopsy specimens obtained from children with chronic hepatitis B showed the presence of two types of oval cells, the hepatic progenitor cells and intermediate hepatic-like cells. These cells were present in the parenchyma and were seen most commonly in areas of intense periportal fibrosis (at least stage 2 according to Ishak et al) and in the vicinity of the limiting plate of the lobule. The activated nonparenchymal hepatic cells, i.e. transformed hepatic stellate cells and Kupffer cells were seen in close proximity to the intermediate hepatic-like cells.
CONCLUSION: We found a distinct relationship between the prevalence of oval cells (hepatic progenitor cells and intermediate hepatocyte-like cells) and fibrosis stage in pediatric patients with chronic hepatitis B.
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Abstract
Until recently, the adult neovasculature was thought to arise only through angiogenesis, the mechanism by which new blood vessels form from preexisting vessels through endothelial cell migration and proliferation. However, recent studies have provided evidence that postnatal neovasculature can also arise though vasculogenesis, a process by which endothelial progenitor cells are recruited and differentiate into mature endothelial cells to form new blood vessels. Evidence for the existence of endothelial progenitors has come from studies demonstrating the ability of bone marrow-derived cells to incorporate into adult vasculature. However, the exact nature of endothelial progenitor cells remains controversial. Because of the lack of definitive markers of endothelial progenitors, the in vivo contribution of progenitor cells to physiological and pathological neovascularization remains unclear. Early studies reported that endothelial progenitor cells actively integrate into the adult vasculature and are critical in the development of many types of vascular-dependent disorders such as neoplastic progression. Moreover, it has been suggested that endothelial progenitor cells can be used as a therapeutic strategy aimed at promoting vascular growth in a variety of ischemic diseases. However, increasing numbers of studies have reported no clear contribution of endothelial progenitors in physiological or pathological angiogenesis. In this chapter, we discuss the origin of the endothelial progenitor cell in the embryo and adult, and we discuss the cell's link to the primitive hematopoietic stem cell. We also review the potential significance of endothelial progenitor cells in the formation of a postnatal vascular network and discuss the factors that may account for the current lack of consensus of the scientific community on this important issue.
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Affiliation(s)
- B Larrivée
- Laboratoire de Médecine Expérimentale, INSERM U36, Collège de France, 11 Place Marcelin Berthelot, 75005 Paris, France
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44
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Sgodda M, Aurich H, Kleist S, Aurich I, König S, Dollinger MM, Fleig WE, Christ B. Hepatocyte differentiation of mesenchymal stem cells from rat peritoneal adipose tissue in vitro and in vivo. Exp Cell Res 2007; 313:2875-86. [PMID: 17574236 DOI: 10.1016/j.yexcr.2007.05.020] [Citation(s) in RCA: 139] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2007] [Revised: 04/13/2007] [Accepted: 05/15/2007] [Indexed: 02/08/2023]
Abstract
Mesenchymal tissues harbour stromal cells capable of multilineage differentiation. Here, we demonstrate the isolation of mesenchymal stem cells (MSC) from rat peritoneal adipose tissue capable of osteogenic and adipogenic differentiation. Under in vitro conditions favouring hepatocyte differentiation, these MSC gained characteristic functions of hepatocytes such as the capacity to synthesize urea or store glycogen. Hepatocyte-specific transcripts of dipeptidylpeptidase type IV (CD26), albumin, cytochrome P450 type 1A1 (CYP1A1) and connexin CX32 (CX32) were detected only in differentiated but not undifferentiated cells. Transient transgenic expression of luciferase could be stimulated by cAMP when driven by the hepatocyte-specific promoter of the cytosolic phosphoenolpyruvate carboxykinase (PCK1) gene. Finally, stem cell-derived hepatocytes from wild type (CD26+/+) rats were transplanted into the livers of CD26-deficient animals after lentiviral transduction with the GFP gene under the control of the ubiquitin promoter. GFP-positive cells engrafted in the host liver predominantly in the periportal region of the liver lobule. They continued to express CD26, a prominent feature of differentiated hepatocytes, indicating their topologically and functionally proper integration into the host liver parenchyma. Thus, MSCs from rat peritoneal adipose tissue exhibit the potential to differentiate into hepatocyte-like cells in vitro and in vivo.
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Affiliation(s)
- Malte Sgodda
- First Department of Medicine, Martin-Luther University of Halle-Wittenberg, Heinrich-Damerow-Strasse 1, Halle/Saale, Germany
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45
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Abstract
BACKGROUND Liver regeneration remains a fascinating topic, still partly clouded to many as to the exact cellular and molecular mechanisms that bring about this phenomenon. It is an area, therefore, of active research today. This review looks at the recent published reports that have led to a greater understanding of this process. METHODS A database search was carried out on Medline search using the terms liver regeneration with no linguistic limitations from 1966 to 2006. RESULTS There are two randomized controlled trials on the topic and most data and information have come from experimental studies in animals. CONCLUSION Liver regeneration is a complex, tightly controlled process involving many inflammatory cells growth factors and hormones. More information about it is awaited in studies on humans.
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Affiliation(s)
- Aamir Z Khan
- Department of Surgery, Royal Marsden Hospital, London, UK.
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46
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Masson NM, Currie IS, Terrace JD, Garden OJ, Parks RW, Ross JA. Hepatic progenitor cells in human fetal liver express the oval cell marker Thy-1. Am J Physiol Gastrointest Liver Physiol 2006; 291:G45-54. [PMID: 16769813 DOI: 10.1152/ajpgi.00465.2005] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatic progenitor cells play a major role in regenerating diseased liver. In rodents, progenitors forming hepatocytes or cholangiocytes are identified by the stem cell marker Thy-1. The aim of this study was to ascertain whether progenitor cells expressing Thy-1 could be identified in human fetal liver. Midtrimester human fetal liver was immunostained for Thy-1, cytokeratins 18 and 19, vimentin, CD34, CD45, and fibrinogen. Thy-1+ and Thy-1+CD34+ populations were purified using fluorescence-activated cell sorting (FACS). Immunofluorescence and mRNA expression were used to examine the bipotential nature of purified stem cells. We found that Thy-1+ cells were concentrated in portal tracts but were also scattered in parenchyma. In FACS-prepared cells, 0.18-3.08% (median 0.65%, n = 14) of cells were Thy-1+. Immunophenotyping revealed that some Thy-1+ cells coexpressed cytokeratins 18 and 19, others, fibrinogen and cytokeratin 19. RT-PCR demonstrated that Thy-1+ cells expressed mRNA for Thy-1, cytokeratin 18, and cytokeratin 19, and Thy-1+CD34+ cells expressed mRNA for alpha-fetoprotein, transferrin, and hepatocyte nuclear factor-4alpha. Thy-1+ cells were identified in fetal liver. These cells expressed several lineage markers, including coexpression of biliary and hepatocellular proteins and mRNA. These data suggest that Thy-1 is a marker of liver stem cells in human fetal liver.
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Affiliation(s)
- Neil M Masson
- Tissue Injury and Repair Group, Department of Clinical and Surgical Sciences (Surgery), University of Edinburgh Medical School, Edinburgh, EH16 4SB, UK.
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Vander Borght S, Libbrecht L, Katoonizadeh A, van Pelt J, Cassiman D, Nevens F, Van Lommel A, Petersen BE, Fevery J, Jansen PL, Roskams TA. Breast cancer resistance protein (BCRP/ABCG2) is expressed by progenitor cells/reactive ductules and hepatocytes and its expression pattern is influenced by disease etiology and species type: possible functional consequences. J Histochem Cytochem 2006; 54:1051-9. [PMID: 16709727 DOI: 10.1369/jhc.5a6912.2006] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette transport protein that is expressed in several organs including the liver. Previous studies have shown that ABC transport proteins play an important pathophysiological role in several liver diseases. However, to date, expression pattern and possible role of BCRP in human liver diseases and animal models have not been studied in detail. Here we investigated the expression pattern of BCRP in normal liver, chronic parenchymal and biliary human liver diseases, and parallel in different rat models of liver diseases. Expression was studied by immunohistochemistry and additionally by RT-PCR analysis in Thy-1-positive rat oval cells. Bile ducts, hepatic progenitor cells, reactive bile ductules, and blood vessel endothelium were immunoreactive for BCRP in normal liver and all types of human liver diseases and in rat models. BCRP was expressed by the canalicular membrane of hepatocytes in normal and diseased human liver, but never in rat liver. Remarkably, there was also expression of BCRP at the basolateral pole of human hepatocytes, and this was most pronounced in chronic biliary diseases. In conclusion, BCRP positivity in the progenitor cells/reactive ductules could contribute to the resistance of these cells to cytotoxic agents and xenotoxins. Basolateral hepatocytic expression in chronic biliary diseases may be an adaptive mechanism to pump bile constituents back into the sinusoidal blood. Strong differences between human and rat liver must be taken into account in future studies with animal models.
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Affiliation(s)
- Sara Vander Borght
- Laboratory of Morphology and Molecular Pathology, University Hospitals Leuven, Belgium.
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Sicklick JK, Li YX, Melhem A, Schmelzer E, Zdanowicz M, Huang J, Caballero M, Fair JH, Ludlow JW, McClelland RE, Reid LM, Diehl AM. Hedgehog signaling maintains resident hepatic progenitors throughout life. Am J Physiol Gastrointest Liver Physiol 2006; 290:G859-70. [PMID: 16322088 DOI: 10.1152/ajpgi.00456.2005] [Citation(s) in RCA: 175] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hedgehog signaling through its receptor, Patched, activates transcription of genes, including Patched, that regulate the fate of various progenitors. Although Hedgehog signaling is required for endodermal commitment and hepatogenesis, the possibility that it regulates liver turnover in adults had not been considered because mature liver epithelial cells lack Hedgehog signaling. Herein, we show that this pathway is essential throughout life for maintaining hepatic progenitors. Patched-expressing cells have been identified among endodermally lineage-restricted, murine embryonic stem cells as well as in livers of fetal and adult Ptc-lacZ mice. An adult-derived, murine hepatic progenitor cell line expresses Patched, and Hedgehog-responsive cells exist in stem cell compartments of fetal and adult human livers. In both species, manipulation of Hedgehog activity influences hepatic progenitor cell survival. Therefore, Hedgehog signaling is conserved in hepatic progenitors from fetal development through adulthood and may be a new therapeutic target in patients with liver damage.
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Affiliation(s)
- Jason K Sicklick
- Division of Gastroenterology, Duke University Medical Center, Snyderman-GSRB I, Suite 1073, 595 LaSalle St., Box 3256, Durham, NC 27710, USA
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Nomoto K, Tsuneyama K, Cheng C, Takahashi H, Hori R, Murai Y, Takano Y. Intrahepatic cholangiocarcinoma arising in cirrhotic liver frequently expressed p63-positive basal/stem-cell phenotype. Pathol Res Pract 2005; 202:71-6. [PMID: 16377099 DOI: 10.1016/j.prp.2005.10.011] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2005] [Accepted: 10/18/2005] [Indexed: 12/15/2022]
Abstract
In general, intrahepatic cholangiocarcinoma (ICC) is not related to liver cirrhosis. However, a few cases have been reported in which ICC was accompanied by severe liver fibrosis. Some researchers have proposed that hepatocellular and cholangiocellular (HC-CC) carcinoma, an intermediate mixed phenotype possibly arising in cirrhotic liver, might originate from hepatic precursor cells. In the liver, hepatocytes and cholangiocytes form the epithelial element, but stromal and mesenchymal elements may be produced by hepatic stem cells. Based on these aspects, not only HC-CC, but also other combinations of cellular phenotypes, would cover all the cancers with stem cell features. In this study, which aimed at determining the characteristics of the ICC phenotype, we used immunohistochemistry to examine the expression of basal/stem-cell markers, i.e., p63 in ICC with and without liver cirrhosis, as well as the expressions of cytokeratin (CK) 34 beta E12, specific for the basal-cell marker, and c-kit, specific for the stem-cell marker. Aberrant p63 was frequently expressed in ICC arising in cirrhotic liver. This result suggests that ICC cancer cells originate from hepatic precursor cells with a hidden multi-differentiation potential.
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Affiliation(s)
- Kazuhiro Nomoto
- Department of Pathology I, Faculty of Medicine, Toyama University, 2630 Sugitani, Toyama-City, Toyama 930-0194, Japan.
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Larrivée B, Niessen K, Pollet I, Corbel SY, Long M, Rossi FM, Olive PL, Karsan A. Minimal contribution of marrow-derived endothelial precursors to tumor vasculature. THE JOURNAL OF IMMUNOLOGY 2005; 175:2890-9. [PMID: 16116175 DOI: 10.4049/jimmunol.175.5.2890] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
During embryogenesis, vascular and hemopoietic cells originate from a common precursor, the hemangioblast. Recent evidence suggests the existence of endothelial precursors in adult bone marrow cells, but it is unclear whether those precursors have a role in tumor neovascularization. In this report, we demonstrate that murine bone marrow contains endothelial progenitors, which arise from a cell with self-renewing capacity, and can integrate into tumor microvasculature, albeit at a very low frequency. A transgenic double-reporter strategy allowed us to demonstrate definitively that tumor bone marrow-derived endothelial cells arise by transdifferentiation of marrow progenitors rather than by cell fusion. Single cell transplants showed that a common precursor contributes to both the hemopoietic and endothelial lineages, thus demonstrating the presence of an adult hemangioblast. Furthermore, we demonstrate that increased vascular endothelial growth factor (VEGF)-A secretion by tumor cells, as well as activation of VEGF receptor-2 in bone marrow cells does not alter the mobilization and incorporation of marrow-derived endothelial progenitors into tumor vasculature. Finally, in human umbilical cord blood cells, we show that endothelial precursors make up only approximately 1 in 10(7) mononuclear cells but are highly enriched in the CD133+ cell population. By ruling out cell fusion, we clearly demonstrate the existence of an adult hemangioblast, but the differentiation of marrow stem cells toward the endothelial lineage is an extremely rare event. Furthermore, we show that VEGF-A stimulation of hemopoietic cells does not significantly alter this process.
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Affiliation(s)
- Bruno Larrivée
- Department of Medicine, University of British Columbia, Canada
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