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Sigot V, Mediavilla MG, Furno G, Rodríguez JV, Guibert EE. A Simple and Effective Method to Improve Intrasplenic Rat Hepatocyte Transplantation. Cell Transplant 2017; 13:775-81. [PMID: 15690979 DOI: 10.3727/000000004783983459] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Transplanted hepatocytes integrate, survive, and express their specific functions in the liver parenchyma. The aim of this study was to determine whether a large number of hepatocytes could move from the spleen to the liver when the cells are injected together with sodium nitroprusside, and if the improved hepatocyte migration may be related with portal vein dilatation. Wistar rats were transplanted in the spleen with fluorescent-labeled hepatocytes alone or together with sodium nitroprusside. At 1, 3, 6, and 24 h after the transplant, the liver from recipient animals was removed and morphometric analyses were performed. Portal and arterial pressures were also measured immediately after intrasplenic injection of a solution of sodium nitroprusside, hepatocytes alone, or hepatocytes plus sodium nitroprusside. Intrasplenically injected sodium nitroprusside produced a transient drop in arterial pressure and a sustained reduction in portal pressure. During hepatocyte transplantation it increased the number of transplanted cells migrating to the liver after 3 h. Sodium nitroprusside simultaneously injected with hepatocytes in the spleen allowed more cells to migrate into the liver of the host animal without risk in animal survival.
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Affiliation(s)
- Valeria Sigot
- Biología Molecular, Dto Cs Biológicas, Facultad de Cs Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, Rosario, Santa Fe, Argentina
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Miki T, Grubbs B. Therapeutic potential of placenta-derived stem cells for liver diseases: current status and perspectives. J Obstet Gynaecol Res 2013; 40:360-8. [PMID: 24245961 DOI: 10.1111/jog.12213] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Accepted: 06/17/2013] [Indexed: 12/15/2022]
Abstract
Over the last decade, there has been a growing interest in the human placenta as a unique source of stem cells. The placenta is a fetal organ that is normally discarded following delivery. Therefore, it is readily available as a source of cells without the ethical concerns normally associated with embryonic stem cells. These cells also carry less risk for age- and environmental-related DNA damage. In addition to these practical advantages of placenta-derived cells, amniotic epithelial cells possess unique stem cell-like biological characteristics. In contrast to other parts of the placenta, cells from the amniotic epithelium are derived from pluripotent epiblasts and possess the ability to differentiate into all three germ layers. From a translational perspective, amnion-derived stem cells are very attractive candidates for clinical application. These cells are genetically stable and do not demonstrate tumorigenicity upon transplantation, and may be endowed with immunomodulatory and/or anti-inflammatory properties. These unique characteristics have made amniotic epithelial cells attractive for use as stem cell-based therapies for liver disease. Human and rodent amniotic epithelial cells have already demonstrated their therapeutic efficacy in multiple animal models. Although the detailed mechanism by which the transplanted cells generate a therapeutic effect is not yet totally understood, these dramatic results have generated significant interest for consideration of these amnion-derived stem cells for clinical applications. This review covers recent findings of the therapeutic potential of amnion-derived stem cells for liver diseases, and provides perspectives for future developments.
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Affiliation(s)
- Toshio Miki
- Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Iwamuro M, Shahid JM, Yamamoto K, Kobayashif N. Prospects for Induced Phiripotent Stem Cell-Derived Hepatocytes in Cell Therapy. CELL MEDICINE 2011; 2:1-8. [PMID: 26998398 DOI: 10.3727/215517911x575975] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Induced pluripotent stem (iPS) cells, first established in 2006, have the same characteristics of self-renew-ability and pluripotency as embryonic stem (ES) cells. iPS cells are inducible from patient-specific somatic cells; therefore, they hold significant advantages for overcoming immunological rejection as well as the ethical issues associated with the derivation of ES cells from embryos. Generation of patient-derived hepatocytes by iPS technology and their use in cell transplantation therapy for patients with liver disease is quite attractive. Here, we discuss recent advances and challenges in hepatocyte differentiation from iPS cells and their utility in cell therapy.
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Affiliation(s)
- Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , Okayama , Japan
| | - Javed M Shahid
- † Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , Okayama , Japan
| | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , Okayama , Japan
| | - Naoya Kobayashif
- † Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences , Okayama , Japan
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Iwamuro M, Komaki T, Kubota Y, Seita M, Kawamoto H, Yuasa T, Shahid JM, Hassan RARA, Hassan WARA, Nakaji S, Nishikawa Y, Kondo E, Yamamoto K, Fox IJ, Kobayashi N. Hepatic differentiation of mouse iPS cells in vitro. Cell Transplant 2010; 19:841-847. [PMID: 20955659 DOI: 10.3727/096368910x508960] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Induced pluripotent stem (iPS) cells are pluripotent and are able to unlimitedly proliferate in vitro. This technical breakthrough in creating iPS cells from somatic cells has noteworthy implications for overcoming the immunological rejection and the ethical issues associated with the derivation of embryonic stem cells from embryos. In the current work, we present an efficient hepatic differentiation of mouse iPS cells in vitro. iPS cells were cultured free floating to induce the formation of embryoid bodies (EB) for 5 days. EB were transferred to a gelatin-coated plate and treated with 100 ng/ml activin A and 100 ng/ml basic fibroblast growth factor (bFGF) for 3 days to induce definitive endoderm. Cells were further cultured for 8 days with 100 ng/ml hepatocyte growth factor (HGF) to generate hepatocytes. Characterization was performed by RT-PCR assay. Functional analysis for albumin secretion and ammonia removal was also carried out. iPS cell-derived hepatocyte-like cells (iPS-Heps) were obtained at the end of the differentiation program. Expression levels of a gestational hepatocyte gene and lineage-specific hepatic genes intensified in iPS-Heps. The production of albumin increased in a time-dependent manner. iPS-Heps were capable of metabolizing ammonia. We present here instant hepatic differentiation of mouse iPS cells using combined 3-day treatments of activin A and bFGF with subsequent 8-day HGF. Our study will be an important step to generate hepatocytes from human iPS cells as a new source for liver-targeted cell therapies.
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Affiliation(s)
- Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
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Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol 2009; 21:1199-205. [PMID: 19455046 DOI: 10.1097/meg.0b013e32832a1f6c] [Citation(s) in RCA: 322] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND End-stage liver disease is a medical problem with high morbidity and mortality. We have investigated the feasibility, safety, and efficacy of using autologous mesenchymal stem cells (MSCs) as a treatment. METHODS Eight patients (four hepatitis B, one hepatitis C, one alcoholic, and two cryptogenic) with end-stage liver disease having Model for End-Stage Liver Disease score > or =10 were included. Autologous MSCs were taken from iliac crest. Approximately, 30-50 million MSCs were proliferated and injected into peripheral or the portal vein. Liver function and clinical features were evaluated at baseline and 1, 2, 4, 8, and 24 weeks after injection. RESULTS Treatment was well tolerated by all patients. Liver function improved as verified by the Model for End-Stage Liver Disease score, which decreased from 17.9+/-5.6 to 10.7+/-6.3 (P<0.05) and prothrombin complex from international normalized ratio 1.9+/-0.4 to 1.4+/-0.5 (P<0.05). Serum creatinine decreased from 114+/-35 to 80+/-18 micromol/l (P<0.05). Serum albumin changed from 30+/-5 to 33+/-5 g/l and bilirubin from 46+/-29 to 41+/-31 micromol/l. No adverse effects were noted. CONCLUSION Our data show that MSCs injection can be used for the treatment of end-stage liver disease with satisfactory tolerability. Furthermore, this treatment may improve clinical indices of liver function in end-stage liver disease.
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Kosone T, Takagi H, Horiguchi N, Kakizaki S, Sato K, Watanabe Y, Mori M. Transforming growth factor-alpha accelerates hepatocyte repopulation after hepatocyte transplantation. J Gastroenterol Hepatol 2008; 23:260-266. [PMID: 17683499 DOI: 10.1111/j.1440-1746.2007.05041.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIM Although hepatocyte transplantation could be an alternative to orthotopic liver transplantation, many problems, such as rejection, location, required volume, and hepatocyte activity are currently unresolved. We previously demonstrated an anti-apoptotic effect in transgenic mice overexpressing transforming growth factor (TGF)-alpha. We herein present the details of a successful hepatocyte transplantation using TGF-alpha transgenic mice. METHODS We used transgenic (TG) mice which overexpressed human TGF-alpha controlled by the metallothionein promoter. Wild-type mice were used as the controls (WT). Parenchymal hepatocytes were isolated from an adult mouse by the modified in situ perfusion method. The proliferation and resistance to Fas-induced apoptosis were examined in vitro. In addition, we transplanted the parenchymal hepatocytes into the peritoneal cavity of the WT mice. RESULTS The TG hepatocytes showed higher proliferative activity and more resistance to Fas-induced apoptosis in comparison to the WT hepatocytes. Moreover, an immunohistochemical analysis demonstrated that the transplanted TG hepatocytes increased more in size and showed a higher expression of CD31 and vascular endothelial growth factor in comparison to the WT hepatocytes. We also observed that albumin was expressed in equal amounts in both types of transplanted hepatocytes. CONCLUSION Cell transplantation with TGF-alpha overexpressing hepatocytes could preserve hepatocyte function.
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Affiliation(s)
- Takashi Kosone
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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Navarro-Alvarez N, Soto-Gutierrez A, Rivas-Carrillo JD, Fox IJ, Tanaka N, Kobayashi N. Stem cell-derived hepatocytes. Curr Opin Organ Transplant 2006; 11:659-664. [DOI: 10.1097/mot.0b013e3280109b7d] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Strom SC, Bruzzone P, Cai H, Ellis E, Lehmann T, Mitamura K, Miki T. Hepatocyte transplantation: clinical experience and potential for future use. Cell Transplant 2006; 15 Suppl 1:S105-10. [PMID: 16826802 DOI: 10.3727/000000006783982395] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Hepatocyte transplantation has been proposed as a method to support patients with liver insufficiency. There are three main areas where the transplantation of isolated hepatocytes has been proposed and used for clinical therapy. Cell transplantation has been used: 1) for temporary metabolic support of patients in end-stage liver failure awaiting whole organ transplantation, 2) as a method to support liver function and facilitate regeneration of the native liver in cases of fulminant hepatic failure, and 3) in a manner similar to gene therapy, as a "cellular therapy" for patients with genetic defects in vital liver functions. We will briefly review the basic research that leads to clinical hepatocyte transplantation, the published clinical experience with this experimental technique, and some possible future uses of hepatocyte transplantation.
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Affiliation(s)
- Stephen C Strom
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Fan Y, Wang XH, Zhang F, Li XC, Wang K, Qian XF. In vivo expression of hepatocyte growth factor promotes differentiation of stem cells from umbilical cord blood into hepatocyte-like cells. Shijie Huaren Xiaohua Zazhi 2006; 14:767-771. [DOI: 10.11569/wcjd.v14.i8.767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the hepatocyte growth factor-induced differentiation of CD34+ hematopoietic stem cells (HSC) from umbilical cord blood into hepatocyte-like cells.
METHODS: Systemic administration of naked plasmid containing HGF cDNA driven under cytomegalovirus promoter (pCMV-HGF) were injected rapidly via the tail vein of the NOD/SCID mice, and the level of HGF protein in the peripheral blood was detected by enzyme-linked immunosorbent assay. CD34+ human hematopoietic stem cells were isolated from umbilical cord blood by magnetic cell sorting method. 20 μL CCl4 was administered into the mice to establish the model of acute liver damage and hepatocyte proliferation. pCMV-HGF injection and/or CD34+ human hematopoietic stem cells transplantation were performed on the model mice. Then the mortality of the mice and liver function recovery status were observed. Human specific mRNA and protein were also detected in the mice by reverse transcription polymerase chain reaction and immunohistochemistry, respectively (RT-PCR).
RESULTS: A remarkable enhancement of human HGF protein level was observed in the peripheral blood of the mice. The mortality and status of liver function were not significantly different between each experiment group. Path-ological examination showed that the mice received combined treatment HGF and HSC had the lightest liver injury, while the liver injury was not markedly different between the mice received HGF and HSC alone. Human albumin mRNA and protein were all expressed in the liver tissues underwent HSC transplantation with or without HGF, while in the mice with HGF injection, there were much more hepatocyte-like cells.
CONCLUSION: Stem cells from umbilical cord blood can differentiate into hepatocyte-like cells, and HGF can promote this process.
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Ishii T, Yasuchika K, Fujii H, Hoppo T, Baba S, Naito M, Machimoto T, Kamo N, Suemori H, Nakatsuji N, Ikai I. In vitro differentiation and maturation of mouse embryonic stem cells into hepatocytes. Exp Cell Res 2005; 309:68-77. [PMID: 16009362 DOI: 10.1016/j.yexcr.2005.05.028] [Citation(s) in RCA: 76] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2005] [Revised: 05/25/2005] [Accepted: 05/29/2005] [Indexed: 01/12/2023]
Abstract
It is difficult to induce the maturation of embryonic stem (ES) cells into hepatocytes in vitro. We previously reported that Thy1-positive mesenchymal cells derived from the mouse fetal liver promote the maturation of hepatic progenitor cells. Here, we isolated alpha-fetoprotein (AFP)-producing cells from mouse ES cells for subsequent differentiation into hepatocytes in vitro by coculture with Thy1-positive cells. ES cells expressing green fluorescent protein (GFP) under the control of an AFP promoter were cultured under serum- and feeder layer-free culture conditions. The proportion of GFP-positive cells plateaued at 41.6 +/- 12.2% (means +/- SD) by day 7. GFP-positive cells, isolated by flow cytometry, were cultured in the presence or absence of Thy1-positive cells as a feeder layer. Isolated GFP-positive cells were stained for AFP, Foxa2, and albumin. The expression of mRNAs encoding tyrosine amino transferase, tryptophan 2,3-dioxygenase, and glucose-6-phosphatase were only detected following coculture with Thy1-positive cells. Following coculture with Thy1-positive cells, the isolated cells produced and stored glycogen. Ammonia clearance activity was also enhanced following coculture. Electron microscopic analysis indicated that the cocultured cells exhibited the morphologic features of mature hepatocytes. In conclusion, coculture with Thy1-positive cells in vitro induced the maturation of AFP-producing cells isolated from ES cell cultures into hepatocytes.
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Affiliation(s)
- Takamichi Ishii
- Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
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Gandillet A, Vidal I, Alexandre E, Audet M, Chenard-Neu MP, Stutzmann J, Heyd B, Jaeck D, Richert L. Experimental models of acute and chronic liver failure in nude mice to study hepatocyte transplantation. Cell Transplant 2005; 14:277-90. [PMID: 16052909 DOI: 10.3727/000000005783983061] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Although hepatocyte transplantation is a promising therapy for acute liver failure in human, there is still a lack of animal models suffering from hepatic injury in which the benefits of hepatocyte transplantation could be evaluated solely, without the bias caused by immunosuppression. As a consequence, the aim of the study was first to develop reproducible models of partial hepatectomy and of thioacetamide (TA)- or Jo2-induced acute liver failure in nude mice. Chronic liver disease was also investigated by repeated injections of sublethal doses of thioacetamide. Survival rates, routine histologic observations, alanin aminotransferase sera content, Ki67, and caspase 3 immunodetection were investigated both after 40% partial hepatectomy and after toxic-induced damages. Liver injuries were more severe and/or precocious in nude mice than in Balb/c mice for a given treatment with a maximum of acute injury obtained 24 h after single toxic injection, and were found to be transitory and reversible within 10 days. Toxics induced apoptosis followed by necrosis, confirming recent published data. Onset of fibrosis leading to reproducible chronic cirrhosis in nude mice correlated with increasing number of Ki67-positive cells, indicating that high levels of cell proliferation occurred. Chronic cirrhosis progressively reversed to fibrosis when the treatment ceased. Preliminary results demonstrated that engrafted xenogeneic hepatocytes could be detected in the host liver by anti-MHC class I immunohistochemistry. Fractions enriched in 2n or 4n hepatocytes by cell sorting using a flow cytometer were equivalent to the unpurified fraction in terms of engraftment in control nude mice or in nude mice subjected to PH. However, in mice suffering from liver injury 24 h after Jo2 or TA treatment, the engraftment of 2n hepatocytes was about twice that of an unpurified hepatocyte population or of a population enriched in 4n hepatocytes.
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Affiliation(s)
- Amaud Gandillet
- Laboratoire de Chirurgie Expérimentale, Fondation Transplantation, 67200 Strasbourg, France
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Wu LM, Li LD, Liu H, Ning KY, Li YK. Effects of Guiyuanfang and autologous transplantation of bone marrow stem cells on rats with liver fibrosis. World J Gastroenterol 2005; 11:1155-60. [PMID: 15754396 PMCID: PMC4250705 DOI: 10.3748/wjg.v11.i8.1155] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [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 therapeutic effects of Guiyuanfang and bone marrow stem cells (BMSCs) on rats with liver fibrosis.
METHODS: Liver fibrosis model was induced by carbon tetrachloride, ethanol, high lipid and assessed biochemically and histologically. Liver function and hydroxyproline contents of liver tissue were determined. Serum hyaluronic acid (HA) level and procollagen III level were performed by radioimmunoassay. The VG staining was used to evaluate the collagen deposit in the liver. Immunohistochemical SABC methods were used to detect transplanted BMSCs and expression of urokinase plasminogen activator (uPA).
RESULTS: Serum transaminase level and liver fibrosis in rats were markedly reduced by Guiyuanfang and BMSCs. HA level and procollagen III level were also reduced obviously, compared to model rats (HA: 47.18±10.97 ng/mL, 48.96±14.79 ng/mL; PCIII: 22.48±5.46 ng/mL, 26.90±3.35 ng/mL; P<0.05). Hydroxyproline contents of liver tissue in both BMSCs group and Guiyuanfang group were far lower than that of model group (1227.2±43.1 μg/g liver tissue, 1390.8±156.3 μg/g liver tissue; P<0.01). After treatment fibrosis scores were also reduced. Both Guiyuanfang and BMSCs could increase the expression of uPA. The transplanted BMSCs could engraft, survive, and proliferate in the liver.
CONCLUSION: Guiyuanfang protects against liver fibrosis. Transplanted BMSCs may engraft, survive, and proliferate in the fibrosis livers indefinitely. Guiyuanfang may synergize with BMSCs to improve recovery from liver fibrosis.
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Affiliation(s)
- Li-Mao Wu
- Institute of Traditional Chinese Materia Medica, College of Pharmaceutical Science, Zhejiang University, Hangzhou 310031, Zhejiang Province, China.
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Theise ND. Liver stem cells: prospects for treatment of inherited and acquired liver diseases. Expert Opin Biol Ther 2003; 3:403-8. [PMID: 12783609 DOI: 10.1517/14712598.3.3.403] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
It is now understood that there are three cell compartments which physiologically contribute to vertebrate liver parenchymal maintenance and regeneration after injury: mature liver cells (hepatocytes, cholangiocytes), intraorgan stem/progenitor cells (cells of the proximal biliary tree, periductal cells) and extraorgan stem cells (from the circulation and the bone marrow). All of these cell populations, as well as other, non-physiologic stem cells (e.g., mesenchymal stromal cells from the bone marrow, fetal hepatoblasts, embryonic stem [ES] cells), may be used therapeutically for treatment of inherited and acquired liver diseases. This article will summarise our current understanding of these various cell populations, and review possible approaches to their therapeutic use, including cell transplantation, bioartificial liver devices (BLDs), gene therapy and administration of exogenous factors to stimulate normal physiological responses to repair.
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Affiliation(s)
- Neil D Theise
- Beth Israel Medical Center, Division of Digestive Diseases, 1st Avenue at 16th Street, New York, NY 10003, USA.
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