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Olivera-Salazar R, Sánchez A, Herrera B, García-Sáez J, Vega-Clemente L, Villarejo Campos P, García-Olmo D, García-Arranz M. A Protocol for the Isolation of Oval Cells without Preconditioning. Int J Mol Sci 2024; 25:10497. [PMID: 39408831 PMCID: PMC11477217 DOI: 10.3390/ijms251910497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Oval cells (OCs) is the name of hepatic progenitor cells (HPCs) in rodents. They are a small population of cells in the liver with the remarkable ability to proliferate and regenerate hepatocytes and cholangiocytes in response to acute liver damage. Isolating OCs generally requires a pretreatment with special diets, chemicals, and/or surgery to induce hepatic damage and OC proliferation in mice. Unfortunately, these pretreatments are not only painful for the mice but also increase the cost of the assays, and the effects on the different organs as well as on various liver cells are still unclear. Therefore, the search for a protocol to obtain OCs without prior liver damage is mandatory. In our study, we present a protocol to isolate murine OCs from healthy liver (HL-OCs) and compare them with OCs isolated from mice pretreated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC-OCs). Our results demonstrated that cells derived from untreated mice exhibited similar behavior to those from treated mice in terms of surface marker expression, proliferation, and differentiation capacity. Therefore, given the impracticability of isolating human cells with prior hepatotoxic treatment, our model holds promise for enabling the isolation of progenitor cells from human tissue in the future. This advancement could prove invaluable for translational medicine in the understanding and treatment of liver diseases.
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Affiliation(s)
- Rocío Olivera-Salazar
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040 Madrid, Spain; (R.O.-S.); (L.V.-C.); (D.G.-O.)
| | - Aránzazu Sánchez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the “Hospital Clínico San Carlos” (IdISSC), 28040 Madrid, Spain; (A.S.); (B.H.); (J.G.-S.)
- Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD-ISCIII), 28029 Madrid, Spain
| | - Blanca Herrera
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the “Hospital Clínico San Carlos” (IdISSC), 28040 Madrid, Spain; (A.S.); (B.H.); (J.G.-S.)
- Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD-ISCIII), 28029 Madrid, Spain
| | - Juan García-Sáez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid (UCM), Health Research Institute of the “Hospital Clínico San Carlos” (IdISSC), 28040 Madrid, Spain; (A.S.); (B.H.); (J.G.-S.)
- Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD-ISCIII), 28029 Madrid, Spain
| | - Luz Vega-Clemente
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040 Madrid, Spain; (R.O.-S.); (L.V.-C.); (D.G.-O.)
| | - Pedro Villarejo Campos
- Department of Surgery, Fundación Jiménez Díaz University Hospital (FJD), 28040 Madrid, Spain;
| | - Damián García-Olmo
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040 Madrid, Spain; (R.O.-S.); (L.V.-C.); (D.G.-O.)
- Department of Surgery, Fundación Jiménez Díaz University Hospital (FJD), 28040 Madrid, Spain;
- Department of Surgery, Universidad Autónoma de Madrid, 28034 Madrid, Spain
| | - Mariano García-Arranz
- New Therapies Laboratory, Health Research Institute-Fundación Jiménez Díaz University Hospital (IIS-FJD), Avda. Reyes Católicos, 2, 28040 Madrid, Spain; (R.O.-S.); (L.V.-C.); (D.G.-O.)
- Department of Surgery, Universidad Autónoma de Madrid, 28034 Madrid, Spain
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Faccioli LA, Dias ML, Martins-Santos R, Paredes BD, Takiya CM, dos Santos Goldenberg RC. Resident Liver Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:23-51. [DOI: 10.1016/b978-0-443-15289-4.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liver Regeneration by Hematopoietic Stem Cells: Have We Reached the End of the Road? Cells 2022; 11:cells11152312. [PMID: 35954155 PMCID: PMC9367594 DOI: 10.3390/cells11152312] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/22/2022] [Accepted: 07/22/2022] [Indexed: 02/01/2023] Open
Abstract
The liver is the organ with the highest regenerative capacity in the human body. However, various insults, including viral infections, alcohol or drug abuse, and metabolic overload, may cause chronic inflammation and fibrosis, leading to irreversible liver dysfunction. Despite advances in surgery and pharmacological treatments, liver diseases remain a leading cause of death worldwide. To address the shortage of donor liver organs for orthotopic liver transplantation, cell therapy in liver disease has emerged as a promising regenerative treatment. Sources include primary hepatocytes or functional hepatocytes generated from the reprogramming of induced pluripotent stem cells (iPSC). Different types of stem cells have also been employed for transplantation to trigger regeneration, including hematopoietic stem cells (HSCs), mesenchymal stromal cells (MSCs), endothelial progenitor cells (EPCs) as well as adult and fetal liver progenitor cells. HSCs, usually defined by the expression of CD34 and CD133, and MSCs, defined by the expression of CD105, CD73, and CD90, are attractive sources due to their autologous nature, ease of isolation and cryopreservation. The present review focuses on the use of bone marrow HSCs for liver regeneration, presenting evidence for an ongoing crosstalk between the hematopoietic and the hepatic system. This relationship commences during embryogenesis when the fetal liver emerges as the crossroads between the two systems converging the presence of different origins of cells (mesoderm and endoderm) in the same organ. Ample evidence indicates that the fetal liver supports the maturation and expansion of HSCs during development but also later on in life. Moreover, the fact that the adult liver remains one of the few sites for extramedullary hematopoiesis—albeit pathological—suggests that this relationship between the two systems is ongoing. Can, however, the hematopoietic system offer similar support to the liver? The majority of clinical studies using hematopoietic cell transplantation in patients with liver disease report favourable observations. The underlying mechanism—whether paracrine, fusion or transdifferentiation or a combination of the three—remains to be confirmed.
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Lai YL, Wang KH, Hsieh HP, Yen WC. Novel FLT3/AURK multikinase inhibitor is efficacious against sorafenib-refractory and sorafenib-resistant hepatocellular carcinoma. J Biomed Sci 2022; 29:5. [PMID: 35062934 PMCID: PMC8781143 DOI: 10.1186/s12929-022-00788-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 01/08/2022] [Indexed: 11/12/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the sixth most common type of cancer and has a high mortality rate worldwide. Sorafenib is the only systemic treatment demonstrating a statistically significant but modest overall survival benefit. We previously have identified the aurora kinases (AURKs) and FMS-like tyrosine kinase 3 (FLT3) multikinase inhibitor DBPR114 exhibiting broad spectrum anti-tumor effects in both leukemia and solid tumors. The purpose of this study was to evaluate the therapeutic potential of DBPR114 in the treatment of advanced HCC. Methods Human HCC cell lines with histopathology/genetic background similar to human HCC tumors were used for in vitro and in vivo studies. Human umbilical vein endothelial cells (HUVEC) were used to evaluate the drug effect on endothelial tube formation. Western blotting, immunohistochemical staining, and mRNA sequencing were employed to investigate the mechanisms of drug action. Xenograft models of sorafenib-refractory and sorafenib-acquired resistant HCC were used to evaluate the tumor response to DBPR114. Results DBPR114 was active against HCC tumor cell proliferation independent of p53 alteration status and tumor grade in vitro. DBPR114-mediated growth inhibition in HCC cells was associated with apoptosis induction, cell cycle arrest, and polyploidy formation. Further analysis indicated that DBPR114 reduced the phosphorylation levels of AURKs and its substrate histone H3. Moreover, the levels of several active-state receptor tyrosine kinases were downregulated by DBPR114, verifying the mechanisms of DBPR114 action as a multikinase inhibitor in HCC cells. DBPR114 also exhibited anti-angiogenic effect, as demonstrated by inhibiting tumor formation in HUVEC cells. In vivo, DBPR114 induced statistically significant tumor growth inhibition compared with the vehicle control in multiple HCC tumor xenograft models. Histologic analysis revealed that the DBPR114 treatment reduced cell proliferation, and induced apoptotic cell death and multinucleated cell formation. Consistent with the histological findings, gene expression analysis revealed that DBPR114-modulated genes were mostly related to the G2/M checkpoint and mitotic spindle assembly. DBPR114 was efficacious against sorafenib-intrinsic and -acquired resistant HCC tumors. Notably, DBPR114 significantly delayed posttreatment tumor regrowth and prolonged survival compared with the regorafenib group. Conclusion Our results indicated that targeting AURK signaling could be a new effective molecular-targeted agent in the treatment of patients with HCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-022-00788-0.
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BMP9 Promotes an Epithelial Phenotype and a Hepatocyte-like Gene Expression Profile in Adult Hepatic Progenitor Cells. Cells 2022; 11:cells11030365. [PMID: 35159174 PMCID: PMC8834621 DOI: 10.3390/cells11030365] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 11/24/2022] Open
Abstract
Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, has emerged as a new player in chronic liver diseases (CLDs). Its levels increase in the fibrotic liver where it promotes fibrogenesis. It also regulates hepatic progenitor cells (oval cells in rodents), a cell population that contributes to repopulate the liver and recover functionality upon severe damage, but it can also be pro-fibrogenic, depending upon the hepatic microenvironment. Here we analyze the effect of chronic exposure to BMP9 in oval cells. We show that cells chronically treated with BMP9 (B9T-OC) display a more epithelial and hepatocyte-like phenotype while acquiring proliferative and survival advantages. Since our previous studies had revealed a functional crosstalk between BMP9 and the HGF/c-Met signaling pathways in oval cells, we analyzed a possible role for HGF/c-Met in BMP9-induced long-term effects. Data evidence that active c-Met signaling is necessary to obtain maximum effects in terms of BMP9-triggered hepatocytic differentiation potential, further supporting functionally relevant cooperation between these pathways. In conclusion, our work reveals a novel action of BMP9 in liver cells and helps elucidate the mechanisms that serve to increase oval cell regenerative potential, which could be therapeutically modulated in CLD.
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So J, Kim A, Lee SH, Shin D. Liver progenitor cell-driven liver regeneration. Exp Mol Med 2020; 52:1230-1238. [PMID: 32796957 PMCID: PMC8080804 DOI: 10.1038/s12276-020-0483-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/08/2020] [Accepted: 06/17/2020] [Indexed: 12/28/2022] Open
Abstract
The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.
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Affiliation(s)
- Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
| | - Angie Kim
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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Vagnozzi RJ, Sargent MA, Lin SCJ, Palpant NJ, Murry CE, Molkentin JD. Genetic Lineage Tracing of Sca-1 + Cells Reveals Endothelial but Not Myogenic Contribution to the Murine Heart. Circulation 2019; 138:2931-2939. [PMID: 29991486 DOI: 10.1161/circulationaha.118.035210] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND The adult mammalian heart displays a cardiomyocyte turnover rate of ≈1%/y throughout postnatal life and after injuries such as myocardial infarction (MI), but the question of which cell types drive this low level of new cardiomyocyte formation remains contentious. Cardiac-resident stem cells marked by stem cell antigen-1 (Sca-1, gene name Ly6a) have been proposed as an important source of cardiomyocyte renewal. However, the in vivo contribution of endogenous Sca-1+ cells to the heart at baseline or after MI has not been investigated. METHODS Here we generated Ly6a gene-targeted mice containing either a constitutive or an inducible Cre recombinase to perform genetic lineage tracing of Sca-1+ cells in vivo. RESULTS We observed that the contribution of endogenous Sca-1+ cells to the cardiomyocyte population in the heart was <0.005% throughout all of cardiac development, with aging, or after MI. In contrast, Sca-1+ cells abundantly contributed to the cardiac vasculature in mice during physiological growth and in the post-MI heart during cardiac remodeling. Specifically, Sca-1 lineage-traced endothelial cells expanded postnatally in the mouse heart after birth and into adulthood. Moreover, pulse labeling of Sca-1+ cells with an inducible Ly6a-MerCreMer allele also revealed a preferential expansion of Sca-1 lineage-traced endothelial cells after MI injury in the mouse. CONCLUSIONS Cardiac-resident Sca-1+ cells are not significant contributors to cardiomyocyte renewal in vivo. However, cardiac Sca-1+ cells represent a subset of vascular endothelial cells that expand postnatally with enhanced responsiveness to pathological stress in vivo.
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Affiliation(s)
- Ronald J Vagnozzi
- Department of Pediatrics (R.J.V., M.A.S., S.-C.J.L., J.D.M.), Cincinnati Children's Hospital Medical Center, OH
| | - Michelle A Sargent
- Department of Pediatrics (R.J.V., M.A.S., S.-C.J.L., J.D.M.), Cincinnati Children's Hospital Medical Center, OH
| | - Suh-Chin J Lin
- Department of Pediatrics (R.J.V., M.A.S., S.-C.J.L., J.D.M.), Cincinnati Children's Hospital Medical Center, OH
| | - Nathan J Palpant
- Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia (N.J.P.)
| | - Charles E Murry
- Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle (C.E.M.)
| | - Jeffery D Molkentin
- Department of Pediatrics (R.J.V., M.A.S., S.-C.J.L., J.D.M.), Cincinnati Children's Hospital Medical Center, OH.,Howard Hughes Medical Institute (J.D.M.), Cincinnati Children's Hospital Medical Center, OH
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Peng D, Yuan H, Liu T, Wang T, Reed-Maldonado AB, Kang N, Banie L, Wang G, Tang Y, He L, Lin G, Lue TF. Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro. J Sex Med 2019; 16:1874-1884. [PMID: 31585805 DOI: 10.1016/j.jsxm.2019.08.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 08/08/2019] [Accepted: 08/19/2019] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Modulating tissue-resident stem and progenitor cells with a non-invasive, mechanobiological intervention is an optimal approach for tissue regeneration. Stem cell antigen-1 (Sca-1) has been identified as a stem cell marker within many organs but never within the penis. AIM To localize and isolate penile stem/progenitor cells (PSPCs) and to evaluate cellular differentiation after exposure to induction medium and microenergy acoustic pulse (MAP) therapy. METHODS Six male Sprague-Dawley rats were used to isolate PSPCs. Isolation was followed by stem cell characterization and differentiation assays. The PSPCs were then treated with MAP (0.033 mJ/mm2, 1 Hz) at various dosages (25, 50, 100, and 200 pulses) and for different durations (1, 2, 4, 6, or 8 hours) in vitro. MAIN OUTCOME MEASURE The PSPCs (Sca-1-positive cells) were isolated using the magnetic-activated cell sorting system. PSPC cellular differentiation was assessed after induction with induction medium and with MAP in vitro. Wnt/β-catenin signaling was also assayed. RESULTS The PSPCs were successfully localized within the penile subtunic and perisinusoidal spaces, and they were successfully isolated using magnetic-activated cell sorting. The stemness of the cells was confirmed by stem cell marker characterization and by multiple differentiation into smooth muscle cells, endothelial cells, adipocytes, and neurons. MAP-induced PSPCs differentiated into smooth muscle cells by activating the Wnt/β-catenin signaling pathway in a time- and dosage-dependent manner. CLINICAL IMPLICATIONS By modulating resident PSPCs, MAP may have utility in the treatment of erectile dysfunction (ED). STRENGTHS & LIMITATIONS This study provides solid evidence in support of microenergy therapies, including both MAP and low-intensity extracorporeal shock wave therapy, for the treatment of ED. Additional studies are needed and should include additional stem cells markers. Furthermore, studies exploring the underling mechanisms for PSPC activation and differentiation are required. CONCLUSION PSPCs were successfully identified, localized, and isolated. Additionally, MAP provoked PSPCs to differentiate into smooth muscle cells via the Wnt/β-catenin signaling pathway. As such, MAP provides a novel method for activating endogenous tissue-resident stem/progenitor cells and might facilitate stem cell regenerative therapy targeting ED. Peng D, Yuan H, Liu T, et al. Smooth Muscle Differentiation of Penile Stem/Progenitor Cells Induced by Microenergy Acoustic Pulses In Vitro. J Sex Med 2019; 16:1874-1884.
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Affiliation(s)
- Dongyi Peng
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA; Department of Urology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Huixing Yuan
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tianshu Liu
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tianyu Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Amanda B Reed-Maldonado
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Ning Kang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Lia Banie
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Guifang Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Yuxin Tang
- Department of Urology, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Leye He
- Department of Urology, Third Xiangya Hospital of Central South University, Changsha, China
| | - Guiting Lin
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA
| | - Tom F Lue
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA.
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Tsuchiya A, Lu WY. Liver stem cells: Plasticity of the liver epithelium. World J Gastroenterol 2019; 25:1037-1049. [PMID: 30862993 PMCID: PMC6406190 DOI: 10.3748/wjg.v25.i9.1037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/21/2019] [Accepted: 01/26/2019] [Indexed: 02/06/2023] Open
Abstract
The liver has a high regenerative capacity after acute liver injury, but this is often impaired during chronic liver injury. The existence of a dedicated liver stem cell population that acts as a source of regeneration during chronic liver injury has been controversial. Recent advances in transgenic models and cellular reprogramming have provided new insights into the plasticity of the liver epithelium and directions for the development of future therapies. This article will highlight recent findings about the cellular source of regeneration during liver injury and the advances in promoting liver regeneration.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate school of medical and dental sciences, Niigata University, Chuo-ku, Niigata 951-8510, Japan
| | - Wei-Yu Lu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, the University of Birmingham, Birmingham B15 2TT, United Kingdom
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Saggi H, Maitra D, Jiang A, Zhang R, Wang P, Cornuet P, Singh S, Locker J, Ma X, Dailey H, Abrams M, Omary MB, Monga SP, Nejak-Bowen K. Loss of hepatocyte β-catenin protects mice from experimental porphyria-associated liver injury. J Hepatol 2019; 70:108-117. [PMID: 30287339 PMCID: PMC6459193 DOI: 10.1016/j.jhep.2018.09.023] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 08/30/2018] [Accepted: 09/18/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Porphyrias result from anomalies of heme biosynthetic enzymes and can lead to cirrhosis and hepatocellular cancer. In mice, these diseases can be modeled by administration of a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes accumulation of porphyrin intermediates, resulting in hepatobiliary injury. Wnt/β-catenin signaling has been shown to be a modulatable target in models of biliary injury; thus, we investigated its role in DDC-driven injury. METHODS β-Catenin (Ctnnb1) knockout (KO) mice, Wnt co-receptor KO mice, and littermate controls were fed a DDC diet for 2 weeks. β-Catenin was exogenously inhibited in hepatocytes by administering β-catenin dicer-substrate RNA (DsiRNA), conjugated to a lipid nanoparticle, to mice after DDC diet and then weekly for 4 weeks. In all experiments, serum and livers were collected; livers were analyzed by histology, western blotting, and real-time PCR. Porphyrin was measured by fluorescence, quantification of polarized light images, and liquid chromatography-mass spectrometry. RESULTS DDC-fed mice lacking β-catenin or Wnt signaling had decreased liver injury compared to controls. Exogenous mice that underwent β-catenin suppression by DsiRNA during DDC feeding also showed less injury compared to control mice receiving lipid nanoparticles. Control livers contained extensive porphyrin deposits which were largely absent in mice lacking β-catenin signaling. Notably, we identified a network of key heme biosynthesis enzymes that are suppressed in the absence of β-catenin, preventing accumulation of toxic protoporphyrins. Additionally, mice lacking β-catenin exhibited fewer protein aggregates, improved proteasomal activity, and reduced induction of autophagy, all contributing to protection from injury. CONCLUSIONS β-Catenin inhibition, through its pleiotropic effects on metabolism, cell stress, and autophagy, represents a novel therapeutic approach for patients with porphyria. LAY SUMMARY Porphyrias are disorders resulting from abnormalities in the steps that lead to heme production, which cause build-up of toxic by-products called porphyrins. Liver is commonly either a source or a target of excess porphyrins, and complications can range from minor abnormalities to liver failure. In this report, we inhibited Wnt/β-catenin signaling in an experimental model of porphyria, which resulted in decreased liver injury. Targeting β-catenin affected multiple components of the heme biosynthesis pathway, thus preventing build-up of porphyrin intermediates. Our study suggests that drugs inhibiting β-catenin activity could reduce the amount of porphyrin accumulation and help alleviate symptoms in patients with porphyria.
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Affiliation(s)
- Harvinder Saggi
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Dhiman Maitra
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - An Jiang
- 2nd Affilitated Hospital, Xi’an Jiaotong University, Xi’an, Chin
| | - Rong Zhang
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Pengcheng Wang
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States
| | - Pamela Cornuet
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Sucha Singh
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
| | - Joseph Locker
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States,Pittsburgh Liver Research Center, Pittsburgh, PA, United States
| | - Xiaochao Ma
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States
| | - Harry Dailey
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, United States
| | - Marc Abrams
- Dicerna Pharmaceuticals, Inc, Cambridge, MA, United States
| | - M. Bishr Omary
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Satdarshan P. Monga
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States,Pittsburgh Liver Research Center, Pittsburgh, PA, United States
| | - Kari Nejak-Bowen
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States; Pittsburgh Liver Research Center, Pittsburgh, PA, United States.
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Ilic Z, Mondal TK, Guest I, Crawford DR, Sell S. Participation of liver stem cells in cholangiocarcinogenesis after aflatoxin B1 exposure of glutathione S-transferase A3 knockout mice. Tumour Biol 2018; 40:1010428318777344. [DOI: 10.1177/1010428318777344] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aflatoxin B1, arguably the most potent human carcinogen, induces liver cancer in humans, rats, trout, ducks, and so on, but adult mice are totally resistant. This resistance is because of a detoxifying enzyme, mouse glutathione S-transferase A3, which binds to and inactivates aflatoxin B1 epoxide, preventing the epoxide from binding to DNA and causing mutations. Glutathione S-transferase A3 or its analog has not been detected in any of the sensitive species, including humans. The generation of a glutathione S-transferase A3 knockout (represented as KO or -/-) mice has allowed us to study the induction of liver cancer in mice by aflatoxin B1. In contrast to the induction of hepatocellular carcinomas in other species, aflatoxin B1 induces cholangiocarcinomas in GSTA3-/- mice. In other species and in knockout mice, the induction of liver cancer is preceded by extensive proliferation of small oval cells, providing additional evidence that oval cells are bipolar stem cells and may give rise to either hepatocellular carcinoma or cholangiocarcinoma depending on the nature of the hepatocarcinogen and the species of animal. The recent development of mouse oval cell lines in our laboratory from aflatoxin B1-treated GSTA3-/- mice should provide a new venue for study of the properties and potential of putative mouse liver stem cells.
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Affiliation(s)
- Zoran Ilic
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | - Tapan K Mondal
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | - Ian Guest
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | | | - Stewart Sell
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
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Leirós L, Dáu JBT, Pinheiro D, Stumbo Machado AC, Thole AA, Cortez EAC, de Carvalho L, de Carvalho SN. Hematopoietic changes in the offspring induced by maternal overweight: Effect on placenta and fetal liver populations. Placenta 2018; 64:7-16. [PMID: 29626983 DOI: 10.1016/j.placenta.2018.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 01/27/2018] [Accepted: 02/05/2018] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Bone marrow cells (BMC) from obese adult mice display an increased apoptosis rate over proliferation. Hematopoietic stem cells (HSC) form all blood cells and are important BMC used in cell therapy. Because it is known that prenatal development can be affected by adverse metabolic epigenetic programming from the maternal organism, this work aimed to investigate the effects of maternal overweight on placenta and fetal liver hematopoietic niches. METHODS Overweight was induced in female mice by overfeeding during lactation. After Swiss females were mated with healthy males, fetuses at 19 dpc (day post conception) and placentas were analyzed. Maternal biometric parameters were compared, and hematopoiesis in the dissociated placenta and fetal liver cells was analyzed by flow cytometry. Placenta morphology and protein content were also studied. RESULTS The model induced accumulation of adipose tissue, weight gain, and maternal hyperglycemia. Placentas from the overfed group (OG) displayed altered morphology, higher carbohydrate and lipid deposition, and increased protein content of fibronectin and PGC-1α. Cytometric analysis showed that placentas from OG presented a higher percentage of circulating macrophages, endothelial progenitor cells, HSC, and progenitor cells. No difference was detected in the percentage of neutrophil granulocytes and total leukocytes or in the proliferation of total cells, HSC, or total leukocytes. With regard to liver analysis of the OG group, there was a significant increase in circulating macrophages, primitive HSC, and oval cells but no difference in hematopoietic progenitor cells, total leukocytes, or leukocyte or total cell proliferation. CONCLUSION Unregulated maternal metabolism can affect hematopoietic populations within the placenta and fetal liver.
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Affiliation(s)
- Luana Leirós
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil
| | - Juliana Barbosa Torreão Dáu
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil
| | - Daphne Pinheiro
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil
| | - Ana Carolina Stumbo Machado
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil
| | - Alessandra Alves Thole
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil
| | - Erika Afonso Costa Cortez
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil
| | - Laís de Carvalho
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil
| | - Simone Nunes de Carvalho
- Laboratory of Stem Cell Research, Department of Histology and Embryology, Institute of Biology Roberto Alcântara Gomes, State University of Rio de Janeiro, UERJ, Brazil.
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13
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Pereyra D, Starlinger P. Shaping the future of liver surgery: Implementation of experimental insights into liver regeneration. Eur Surg 2018; 50:132-136. [PMID: 29875802 PMCID: PMC5968067 DOI: 10.1007/s10353-018-0515-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/07/2018] [Indexed: 02/07/2023]
Abstract
Background While liver surgery has become a safe and feasible operation technique, the incidence of postoperative liver dysfunction still remains a central problem. Approximately 10% of patients undergoing liver resection were shown to develop liver dysfunction, which is associated with an increased risk of morbidity and mortality. Yet, to date there is no effective treatment option for postoperative liver dysfunction available. The development of postoperative liver dysfunction was linked to a disruption in the liver's potential to regenerate. Thus, it is importance to elucidate the underlying mechanisms of liver regeneration and to find potential therapeutic targets for the treatment of patients with postoperative liver dysfunction. Methods A review of the literature was carried out. Results We report on potential future interventions for improvement of liver regeneration after surgical resection. Moreover, we evaluate the benefits and drawbacks of hepatic progenitor cell therapy and hematopoietic stem cell therapy. However, the most significant improvement seems to come from molecular targets. Indeed, von Willebrand factor and its pharmacologic manipulation are among the most promising therapeutic targets to date. Furthermore, using the example of platelet-based therapy, we stress the potentially adverse effects of treatments for postoperative liver dysfunction. Conclusion The present review reports on the newest advances in the field of regenerative science, but also underlines the need for more research in the field of postoperative liver regeneration, especially in regard to translational studies.
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Affiliation(s)
- D. Pereyra
- Department of Surgery, General Hospital, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
| | - P. Starlinger
- Department of Surgery, General Hospital, Medical University of Vienna, Währinger Gürtel 18–20, 1090 Vienna, Austria
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14
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Crawford DR, Ilic Z, Guest I, Milne GL, Hayes JD, Sell S. Characterization of liver injury, oval cell proliferation and cholangiocarcinogenesis in glutathione S-transferase A3 knockout mice. Carcinogenesis 2017; 38:717-727. [PMID: 28535182 DOI: 10.1093/carcin/bgx048] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
We recently generated glutathione S-transferase (GST) A3 knockout (KO) mice as a novel model to study the risk factors for liver cancer. GSTA3 KO mice are sensitive to the acute cytotoxic and genotoxic effects of aflatoxin B1 (AFB1), confirming the crucial role of GSTA3 in resistance to AFB1. We now report histopathological changes, tumor formation, biochemical changes and gender response following AFB1 treatment as well as the contribution of oxidative stress. Using a protocol of weekly 0.5 mg AFB1/kg administration, we observed extensive oval (liver stem) cell (OC) proliferation within 1-3 weeks followed by microvesicular lipidosis, megahepatocytes, nuclear inclusions, cholangiomas and small nodules. Male and female GSTA3 KO mice treated with 12 and 24 weekly AFB1 injections followed by a rest period of 12 and 6 months, respectively, all had grossly distorted livers with macro- and microscopic cysts, hepatocellular nodules, cholangiomas and cholangiocarcinomas and OC proliferation. We postulate that the prolonged AFB1 treatment leads to inhibition of hepatocyte proliferation, which is compensated by OC proliferation and eventually formation of cholangiocarcinoma (CCA). At low-dose AFB1, male KO mice showed less extensive acute liver injury, OC proliferation and AFB1-DNA adducts than female KO mice. There were no significant compensatory changes in KO mice GST subunits, GST enzymatic activity, epoxide hydrolase, or CYP1A2 and CYP3A11 levels. Finally, there was a modest increase in F2-isoprostane and isofuran in KO mice that confirmed putative GSTA3 hydroperoxidase activity in vivo for the first time.
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Affiliation(s)
- Dana R Crawford
- Albany Medical Center, Department of Immunology and Microbial Disease, 43 New Scotland Avenue, Albany, NY 12208, USA
| | - Zoran Ilic
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
| | - Ian Guest
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
| | - Ginger L Milne
- Vanderbilt University School of Medicine, Department of Medicine and Pharmacology, Nashville, TN 37323, USA
| | - John D Hayes
- Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK
| | - Stewart Sell
- Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA
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15
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Bria A, Marda J, Zhou J, Sun X, Cao Q, Petersen BE, Pi L. Hepatic progenitor cell activation in liver repair. LIVER RESEARCH (BEIJING, CHINA) 2017; 1:81-87. [PMID: 29276644 PMCID: PMC5739327 DOI: 10.1016/j.livres.2017.08.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.
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Affiliation(s)
- Adam Bria
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Jorgessen Marda
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Junmei Zhou
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Xiaowei Sun
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Qi Cao
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Bryon E. Petersen
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Liya Pi
- Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
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16
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Chen J, Chen L, Zern MA, Theise ND, Diehl AM, Liu P, Duan Y. The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver Int 2017; 37:1260-1271. [PMID: 28135758 PMCID: PMC5534384 DOI: 10.1111/liv.13377] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2016] [Accepted: 01/23/2017] [Indexed: 12/12/2022]
Abstract
The liver is a unique organ for homoeostasis with regenerative capacities. Hepatocytes possess a remarkable capacity to proliferate upon injury; however, in more severe scenarios liver regeneration is believed to arise from at least one, if not several facultative hepatic progenitor cell compartments. Newly identified pericentral stem/progenitor cells residing around the central vein is responsible for maintaining hepatocyte homoeostasis in the uninjured liver. In addition, hepatic progenitor cells have been reported to contribute to liver fibrosis and cancers. What drives liver homoeostasis, regeneration and diseases is determined by the physiological and pathological conditions, and especially the hepatic progenitor cell niches which influence the fate of hepatic progenitor cells. The hepatic progenitor cell niches are special microenvironments consisting of different cell types, releasing growth factors and cytokines and receiving signals, as well as the extracellular matrix (ECM) scaffold. The hepatic progenitor cell niches maintain and regulate stem cells to ensure organ homoeostasis and regeneration. In recent studies, more evidence has been shown that hepatic cells such as hepatocytes, cholangiocytes or myofibroblasts can be induced to be oval cell-like state through transitions under some circumstance, those transitional cell types as potential liver-resident progenitor cells play important roles in liver pathophysiology. In this review, we describe and update recent advances in the diversity and plasticity of hepatic progenitor cell and their niches and discuss evidence supporting their roles in liver homoeostasis, regeneration, fibrosis and cancers.
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Affiliation(s)
- Jiamei Chen
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
- E-institutes of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
| | - Long Chen
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mark A Zern
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
| | - Neil D. Theise
- Departments of Pathology and Medicine, Beth Israel Medical Center of Albert Einstein College of Medicine, New York, New York, USA
| | - Ann Mae Diehl
- Division of Gastroenterology, Duke University Medical Center, Durham, North Carolina, USA
| | - Ping Liu
- Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases of Ministry of Education of China, Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai key laboratory of Traditional Chinese Medicine, Shanghai 201203, China
- E-institutes of Shanghai Municipal Education Commission, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuyou Duan
- Department of Internal Medicine, University of California Davis Medical Center, Sacramento, California, USA
- Institute for Regenerative Cures, University of California Davis Medical Center, Sacramento, California, USA
- Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA
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17
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Lee CW, Huang WC, Huang HD, Huang YH, Ho JH, Yang MH, Yang VW, Lee OK. DNA Methyltransferases Modulate Hepatogenic Lineage Plasticity of Mesenchymal Stromal Cells. Stem Cell Reports 2017; 9:247-263. [PMID: 28602611 PMCID: PMC5511371 DOI: 10.1016/j.stemcr.2017.05.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 05/04/2017] [Accepted: 05/05/2017] [Indexed: 12/20/2022] Open
Abstract
The irreversibility of developmental processes in mammalian cells has been challenged by rising evidence that de-differentiation of hepatocytes occurs in adult liver. However, whether reversibility exists in mesenchymal stromal cell (MSC)-derived hepatocytes (dHeps) remains elusive. In this study, we find that hepatogenic differentiation (HD) of MSCs is a reversible process and is modulated by DNA methyltransferases (DNMTs). DNMTs are regulated by transforming growth factor β1 (TGFβ1), which in turn controls hepatogenic differentiation and de-differentiation. In addition, a stepwise reduction in TGFβ1 concentrations in culture media increases DNMT1 and decreases DNMT3 in primary hepatocytes (Heps) and confers Heps with multi-differentiation potentials similarly to MSCs. Hepatic lineage reversibility of MSCs and lineage conversion of Heps are regulated by DNMTs in response to TGFβ1. This previously unrecognized TGFβ1-DNMTs-MSC-HD axis may further increase the understanding the normal and pathological processes in the liver, as well as functions of MSCs after transplantation to treat liver diseases.
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Affiliation(s)
- Chien-Wei Lee
- Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan
| | - Wei-Chih Huang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu 30010, Taiwan
| | - Hsien-Da Huang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, HsinChu 30010, Taiwan; Department of Biological Science and Technology, National Chiao Tung University, HsinChu 30010, Taiwan; Center for Bioinformatics Research, National Chiao Tung University, HsinChu 30010, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11221, Taiwan
| | - Jennifer H Ho
- Center for Stem Cell Research, Taipei Medical University-Wan Fang Hospital, Taipei 11031, Taiwan
| | - Muh-Hwa Yang
- Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei 11221, Taiwan; Genome Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Immunity and Inflammation Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
| | - Vincent W Yang
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Oscar K Lee
- Taipei City Hospital, Taipei 10341, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan; Stem Cell Research Center, National Yang-Ming University, Taipei 11221, Taiwan; Department of Medical Research, Taipei Veterans General Hospital, Taipei 11221, Taiwan.
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18
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Sia D, Villanueva A, Friedman SL, Llovet JM. Liver Cancer Cell of Origin, Molecular Class, and Effects on Patient Prognosis. Gastroenterology 2017; 152:745-761. [PMID: 28043904 DOI: 10.1053/j.gastro.2016.11.048] [Citation(s) in RCA: 804] [Impact Index Per Article: 100.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 11/09/2016] [Accepted: 11/26/2016] [Indexed: 12/11/2022]
Abstract
Primary liver cancer is the second leading cause of cancer-related death worldwide and therefore a major public health challenge. We review hypotheses of the cell of origin of liver tumorigenesis and clarify the classes of liver cancer based on molecular features and how they affect patient prognosis. Primary liver cancer comprises hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), and other rare tumors, notably fibrolamellar carcinoma and hepatoblastoma. The molecular and clinical features of HCC versus iCCA are distinct, but these conditions have overlapping risk factors and pathways of oncogenesis. A better understanding of the cell types originating liver cancer can aid in exploring molecular mechanisms of carcinogenesis and therapeutic options. Molecular studies have identified adult hepatocytes as the cell of origin. These cells have been proposed to transform directly into HCC cells (via a sequence of genetic alterations), to dedifferentiate into hepatocyte precursor cells (which then become HCC cells that express progenitor cell markers), or to transdifferentiate into biliary-like cells (which give rise to iCCA). Alternatively, progenitor cells also give rise to HCCs and iCCAs with markers of progenitor cells. Advances in genome profiling and next-generation sequencing have led to the classification of HCCs based on molecular features and assigned them to categories such as proliferation-progenitor, proliferation-transforming growth factor β, and Wnt-catenin β1. iCCAs have been assigned to categories of proliferation and inflammation. Overall, proliferation subclasses are associated with a more aggressive phenotype and poor outcome of patients, although more specific signatures have refined our prognostic abilities. Analyses of genetic alterations have identified those that might be targeted therapeutically, such as fusions in the FGFR2 gene and mutations in genes encoding isocitrate dehydrogenases (in approximately 60% of iCCAs) or amplifications at 11q13 and 6p21 (in approximately 15% of HCCs). Further studies of these alterations are needed before they can be used as biomarkers in clinical decision making.
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Affiliation(s)
- Daniela Sia
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Scott L Friedman
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Hematology, and Medical Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Translational Research Laboratory, BCLC, Liver Unit, CIBEREHD, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.
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19
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Lukacs-Kornek V, Lammert F. The progenitor cell dilemma: Cellular and functional heterogeneity in assistance or escalation of liver injury. J Hepatol 2017; 66:619-630. [PMID: 27826058 DOI: 10.1016/j.jhep.2016.10.033] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Revised: 10/18/2016] [Accepted: 10/31/2016] [Indexed: 12/16/2022]
Abstract
Liver progenitor cells (LPCs) are quiescent cells that are activated during liver injury and thought to give rise to hepatocytes and cholangiocytes in order to support liver regeneration and tissue restitution. While hepatocytes are capable of self-renewal, during most chronic injuries the proliferative capacity of hepatocytes is inhibited, thus LPCs provide main source for regeneration. Despite extensive lineage tracing studies, their role and involvement in these processes are often controversial. Additionally, increasing evidence suggests that the LPC compartment consists of heterogeneous cell populations that are actively involved in cellular interactions with myeloid and lymphoid cells during regeneration. On the other hand, LPC expansion has been associated with an increased fibrogenic response, raising concerns about the therapeutic use of these cells. This review aims to summarize the current understanding of the identity, the cellular interactions and the key pathways affecting the biology of LPCs. Understanding the regulatory circuits and the specific role of LPCs is especially important as it could provide novel therapeutic platforms for the treatment of liver inflammation, fibrosis and regeneration.
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Affiliation(s)
- Veronika Lukacs-Kornek
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
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20
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Lakhi NA, Mizejewski GJ. Alpha-fetoprotein and Fanconi Anemia: Relevance to DNA Repair and Breast Cancer Susceptibility. Fetal Pediatr Pathol 2017; 36:49-61. [PMID: 27690720 DOI: 10.1080/15513815.2016.1225873] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Elevations of serum alpha-fetoprotein (sAFP) have been reported in fetal and infant states of anemia. Fanconi anemia (FA) belongs to a family of genetic instability disorders which lack the capability to repair DNA breaks. The lesion occurs at a checkpoint regulatory step of the G2 to mitotic transition, allowing FA cells to override cell-cycle arrest. FA DNA repair pathways contain complementation groups known as FANC proteins. FANC proteins form multi-protein complexes with BRCA proteins and are involved in homologous DNA repair. An impaired cascade in these events imparts an increased breast cancer susceptibility to female FA patients. Elevations of sAFP have availed this fetal protein to serve as a biomarker for FA disease. However, the origin of the synthesis of sAFA has not been determined in FA patients. We hypothesize that hematopoietic multipotent progenitor stem cells in the bone marrow are the source of sAFP production in FA patients.
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Affiliation(s)
- Nisha A Lakhi
- a Department of Obstetrics and Gynecology , Richmond University Medical Center , Staten Island , New York , USA
| | - Gerald J Mizejewski
- b Wadsworth Center , New York State Department of Health , Albany , New York , USA
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21
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Kopp JL, Grompe M, Sander M. Stem cells versus plasticity in liver and pancreas regeneration. Nat Cell Biol 2016; 18:238-45. [PMID: 26911907 DOI: 10.1038/ncb3309] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cell replacement in adult organs can be achieved through stem cell differentiation or the replication or transdifferentiation of existing cells. In the adult liver and pancreas, stem cells have been proposed to replace tissue cells, particularly following injury. Here we review how specialized cell types are produced in the adult liver and pancreas. Based on current evidence, we propose that the plasticity of differentiated cells, rather than stem cells, accounts for tissue repair in both organs.
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Affiliation(s)
- Janel L Kopp
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
| | - Markus Grompe
- Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
| | - Maike Sander
- Department of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California 92093-0695, USA
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22
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Zhang H, Siegel CT, Shuai L, Lai J, Zeng L, Zhang Y, Lai X, Bie P, Bai L. Repair of liver mediated by adult mouse liver neuro-glia antigen 2-positive progenitor cell transplantation in a mouse model of cirrhosis. Sci Rep 2016; 6:21783. [PMID: 26905303 PMCID: PMC4764864 DOI: 10.1038/srep21783] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 02/01/2016] [Indexed: 02/07/2023] Open
Abstract
NG2-expressing cells are a population of periportal vascular stem/progenitors (MLpvNG2(+) cells) that were isolated from healthy adult mouse liver by using a "Percoll-Plate-Wait" procedure. We demonstrated that isolated cells are able to restore liver function after transplantation into a cirrhotic liver, and co-localized with the pericyte marker (immunohistochemistry: PDGFR-β) and CK19. Cells were positive for: stem cell (Sca-1, CD133, Dlk) and liver stem cell markers (EpCAM, CD14, CD24, CD49f); and negative for: hematopoietic (CD34, CD45) and endothelial markers (CD31, vWf, von Willebrand factor). Cells were transplanted (1 × 10(6) cells) in mice with diethylnitrosamine-induced cirrhosis at week 6. Cells showed increased hepatic associated gene expression of alpha-fetoprotein (AFP), Albumin (Alb), Glucose-6-phosphatase (G6Pc), SRY (sex determining region Y)-box 9 (Sox9), hepatic nuclear factors (HNF1a, HNF1β, HNF3β, HNF4α, HNF6, Epithelial cell adhesion molecule (EpCAM), Leucine-rich repeated-containing G-protein coupled receptor 5-positive (Lgr5) and Tyrosine aminotransferase (TAT). Cells showed decreased fibrogenesis, hepatic stellate cell infiltration, Kupffer cells and inflammatory cytokines. Liver function markers improved. In a cirrhotic liver environment, cells could differentiate into hepatic lineages. In addition, grafted MLpvNG2(+) cells could mobilize endogenous stem/progenitors to participate in liver repair. These results suggest that MLpvNG2(+) cells may be novel adult liver progenitors that participate in liver regeneration.
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Affiliation(s)
- Hongyu Zhang
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Christopher T. Siegel
- Department of Surgery, Division of Hepatobiliary and Abdominal Organ Transplantation, Case Western Reserve University Hospital, Cleveland OH 44106, USA
| | - Ling Shuai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Jiejuan Lai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Linli Zeng
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Yujun Zhang
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Xiangdong Lai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Ping Bie
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
| | - Lianhua Bai
- Hepatobiliary Institute, Southwestern Hospital, No. 30 Gaotanyan, ShapingBa Distract, Chongqing 400038, China
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Aydin MM, Bayin NS, Acun T, Yakicier MC, Akçali KC. Role of FLT3 in the proliferation and aggressiveness of hepatocellular carcinoma. Turk J Med Sci 2016; 46:572-81. [PMID: 27511526 DOI: 10.3906/sag-1501-173] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Accepted: 05/26/2015] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND/AIM Previously we showed that Fms-like tyrosine kinase (FLT3) changes its cellular localization upon partial hepatectomy, suggesting a role in liver regeneration. FLT3 was also shown to play an important function in cellular proliferation and activation of PI3K and Ras. Thus, we aimed to investigate the role of FLT3 in hepatocellular tumorigenesis utilizing in vitro and in vivo models. MATERIALS AND METHODS We used Snu398 cells that express FLT3. We investigated these cells' in vitro proliferation and invasion abilities by treatment with the FLT3 inhibitor K-252a or by knocking-down with FLT3 shRNA,. Furthermore, the effect of blocking FLT3 activity and expression during in vivo tumorigenesis was assessed with xenograft models. RESULTS After K-252a treatment or stable knock-down, these cells' proliferation and migration abilities were highly diminished in vitro. In addition, significant diminution in tumorigenicity of Snu398 cells was also obtained in vivo. When FLT3 knocked-down Snu398 cells were injected into nude mice, we did not detect αSMA expression in these tumors, suggesting a role for FLT3 in in vivo invasiveness. CONCLUSION Our data provided evidence that FLT3 has a crucial role both in hepatocarcinogenesis and its invasiveness. Therefore, targeting FLT3 and/or its activity may be a promising tool for combating hepatocellular carcinomas.
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Affiliation(s)
- Muammer Merve Aydin
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Nermin Sumru Bayin
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Tolga Acun
- Department of Molecular Biology and Genetics, Faculty of Sciences and Arts, Bülent Ecevit University, Zonguldak, Turkey
| | | | - Kamil Can Akçali
- Department of Biophysics, Ankara University, Faculty of Medicine, Ankara, Turkey
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Köhn-Gaone J, Gogoi-Tiwari J, Ramm GA, Olynyk JK, Tirnitz-Parker JEE. The role of liver progenitor cells during liver regeneration, fibrogenesis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2016; 310:G143-54. [PMID: 26608186 DOI: 10.1152/ajpgi.00215.2015] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 11/19/2015] [Indexed: 01/31/2023]
Abstract
The growing worldwide challenge of cirrhosis and hepatocellular carcinoma due to increasing prevalence of excessive alcohol consumption, viral hepatitis, obesity, and the metabolic syndrome has sparked interest in stem cell-like liver progenitor cells (LPCs) as potential candidates for cell therapy and tissue engineering, as an alternative approach to whole organ transplantation. However, LPCs always proliferate in chronic liver diseases with a predisposition to cancer; they have been suggested to play major roles in driving fibrosis, disease progression, and may even represent tumor-initiating cells. Hence, a greater understanding of the factors that govern their activation, communication with other hepatic cell types, and bipotential differentiation as opposed to their potential transformation is needed before their therapeutic potential can be harnessed.
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Affiliation(s)
- Julia Köhn-Gaone
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia
| | - Jully Gogoi-Tiwari
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia
| | - Grant A Ramm
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - John K Olynyk
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia; Fiona Stanley and Fremantle Hospitals, Western Australia, Australia; School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia; and
| | - Janina E E Tirnitz-Parker
- Curtin Health Innovation Research Institute, Curtin University, Perth Western Australia, Australia; School of Medicine and Pharmacology, University of Western Australia, Fremantle Western Australia, Australia
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25
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Eckert C, Kim YO, Julich H, Heier EC, Klein N, Krause E, Tschernig T, Kornek M, Lammert F, Schuppan D, Lukacs-Kornek V. Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1-12. [PMID: 26564718 PMCID: PMC4698439 DOI: 10.1152/ajpgi.00344.2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 11/05/2015] [Indexed: 01/31/2023]
Abstract
Podoplanin/gp38(+) stromal cells present in lymphoid organs play a central role in the formation and reorganization of the extracellular matrix and in the functional regulation of immune responses. Gp38(+) cells are present during embryogenesis and in human livers of primary biliary cirrhosis. Since little is known about their function, we studied gp38(+) cells during chronic liver inflammation in models of biliary and parenchymal liver fibrosis and steatohepatitis. Gp38(+) cells were analyzed using flow cytometry and confocal microscopy, and the expression of their steady state and inflammation-associated genes was evaluated from healthy and inflamed livers. Gp38(+) cells significantly expanded in all three models of liver injury and returned to baseline levels during regression of inflammation. Based on CD133 and gp38 expression in the CD45(-)CD31(-)Asgpr1(-) liver cell fraction, numerous subsets could be identified that were negative for CD133 (gp38(hi)CD133(-), gp38(low)CD133(-), and gp38(-)CD133(-)). Moreover, among the CD133(+) cells, previously identified as progenitor population in injured liver, two subpopulations could be distinguished based on their gp38 expression (gp38(-)CD133(+) and CD133(+)gp38(+)). Importantly, the distribution of the identified subsets in inflammation illustrated injury-specific changes. Moreover, the gp38(+)CD133(+) cells exhibited liver progenitor cell characteristics similar to the gp38(-)CD133(+) population, thus representing a novel subset within the classical progenitor cell niche. Additionally, these cells expressed distinct sets of inflammatory genes during liver injury. Our study illuminates a novel classification of the stromal/progenitor cell compartment in the liver and pinpoints a hitherto unrecognized injury-related alteration in progenitor subset composition in chronic liver inflammation and fibrosis.
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MESH Headings
- AC133 Antigen
- ATP Binding Cassette Transporter, Subfamily B/deficiency
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Animals
- Antigens, CD/metabolism
- Biomarkers/metabolism
- Cell Separation/methods
- Cells, Cultured
- Chemical and Drug Induced Liver Injury/genetics
- Chemical and Drug Induced Liver Injury/metabolism
- Chemical and Drug Induced Liver Injury/pathology
- Flow Cytometry
- Gene Expression Regulation
- Glycoproteins/metabolism
- Inflammation Mediators/metabolism
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Experimental/genetics
- Liver Cirrhosis, Experimental/metabolism
- Liver Cirrhosis, Experimental/pathology
- Male
- Membrane Glycoproteins/metabolism
- Mice, Inbred C57BL
- Mice, Knockout
- Microscopy, Confocal
- Non-alcoholic Fatty Liver Disease/genetics
- Non-alcoholic Fatty Liver Disease/metabolism
- Non-alcoholic Fatty Liver Disease/pathology
- Peptides/metabolism
- Phenotype
- Stem Cells/metabolism
- Stem Cells/pathology
- Stromal Cells/metabolism
- Stromal Cells/pathology
- ATP-Binding Cassette Sub-Family B Member 4
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Affiliation(s)
- Christoph Eckert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Henrike Julich
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Eva-Carina Heier
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Niklas Klein
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Elmar Krause
- Department of Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Saarland, Germany
| | - Thomas Tschernig
- Insitute of Anatomy and Cell Biology, University of Saarland, Saarland, Germany; and
| | - Miroslaw Kornek
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
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26
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Eom YW, Kim G, Baik SK. Mesenchymal stem cell therapy for cirrhosis: Present and future perspectives. World J Gastroenterol 2015; 21:10253-10261. [PMID: 26420953 PMCID: PMC4579873 DOI: 10.3748/wjg.v21.i36.10253] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 06/01/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis occurs as a result of various chronic liver injuries, which may be caused by viral infections, alcohol abuse and the administration of drugs and chemicals. Recently, bone marrow cells (BMCs), hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) have been used for developing treatments for cirrhosis. Clinical trials have investigated the therapeutic potential of BMCs, HSCs and MSCs for the treatment of cirrhosis based on their potential to differentiate into hepatocytes. Although the therapeutic mechanisms of BMC, HSC and MSC treatments are still not fully characterized, the evidence thus far has indicated that the potential therapeutic mechanisms of MSCs are clearer than those of BMCs or HSCs with respect to liver regenerative medicine. MSCs suppress inflammatory responses, reduce hepatocyte apoptosis, increase hepatocyte regeneration, reverse liver fibrosis and enhance liver functionality. This paper summarizes the clinical studies that have used BMCs, HSCs and MSCs in patients with liver failure or cirrhosis. We also present the potential therapeutic mechanisms of BMCs, HSCs and MSCs for the improvement of liver function.
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27
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Abstract
In recent years, hepatic oval cells (HOC) have gradually become a research hotspot, and their participation in the reconstruction of liver structure and function has been preliminarily confirmed. This provides a new direction for the study of the pathogenesis and treatment of liver injury, hepatitis, liver fibrosis, cirrhosis, liver neoplasms and other liver diseases. This paper will discuss the relationship between hepatic oval cells and liver diseases.
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Katoonizadeh A, Poustchi H, Malekzadeh R. Hepatic progenitor cells in liver regeneration: current advances and clinical perspectives. Liver Int 2014; 34:1464-1472. [PMID: 24750779 DOI: 10.1111/liv.12573] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 04/17/2014] [Indexed: 12/12/2022]
Abstract
When there is a massive loss of hepatocytes and/or an inhibition in the proliferative capacity of the mature hepatocytes, activation of a dormant cell population of resident hepatic progenitor cells (HPCs) occurs. Depending on the type of liver damage HPCs generate new hepatocytes and biliary cells to repopulate the liver placing them as potential candidates for cell therapy in human liver failure. Liver injury specific mechanisms through which HPCs differentiate towards mature epithelial cell types are recently become understood. Such new insights will enable us not only to direct HPCs behaviour for therapeutic purposes, but also to develop clinically feasible methods for in vivo differentiation of other stem cell types towards functional hepatocytes. This review aimed to provide the current improved knowledge of the role of HPCs niche and its signals in directing the behaviour and fate of HPCs and to translate this basic knowledge of HPCs activation/differentiation into its clinical applications.
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Affiliation(s)
- Aezam Katoonizadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Blagodatski A, Poteryaev D, Katanaev VL. Targeting the Wnt pathways for therapies. MOLECULAR AND CELLULAR THERAPIES 2014; 2:28. [PMID: 26056595 PMCID: PMC4452063 DOI: 10.1186/2052-8426-2-28] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2014] [Accepted: 09/05/2014] [Indexed: 12/16/2022]
Abstract
The Wnt/β-catenin signaling pathway is crucial in animal development from sponges to humans. Its activity in the adulthood is less general, with exceptions having huge medical importance. Namely, improper activation of this pathway is carcinogenic in many tissues, most notably in the colon, liver and the breast. On the other hand, the Wnt/β-catenin signaling must be re-activated in cases of tissue damage, and insufficient activation results in regeneration failure and degeneration. These both medically important implications are unified by the emerging importance of this signaling pathway in the control of proliferation of various types of stem cells, crucial for tissue regeneration and, in case of cancer stem cells – cancer progression and relapse. This article aims at briefly reviewing the current state of knowledge in the field of Wnt signaling, followed by a detailed discussion of current medical developments targeting distinct branches of the Wnt pathway for anti-cancer and pro-regeneration therapies.
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Affiliation(s)
- Artem Blagodatski
- Institute of Protein Research, Russian Academy of Sciences, Pushchino, Russian Federation
| | | | - Vladimir L Katanaev
- Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
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30
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Abstract
Stem cells constitute a population of "primitive cells" with the ability to divide indefinitely and give rise to specialized cells under special conditions. Because of these two characteristics they have received particular attention in recent decades. These cells are the primarily responsible factors for the regeneration of tissues and organs and for the healing of lesions, a feature that makes them a central key in the development of cell-based medicine, called Regenerative Medicine. The idea of wound and organ repair and body regeneration is as old as the mankind, reflecting the human desire for inhibiting aging and immortality and it is first described in the ancient Greek myth of Prometheus. It is of interest that the myth refers to liver, an organ with remarkable regenerative ability after loss of mass and function caused by liver injury or surgical resection. Over the last decade there has been an important progress in understanding liver physiology and the mechanisms underlying hepatic development and regeneration. As liver transplantation, despite its difficulties, remains the only effective therapy for advanced liver disease so far, scientific interest has nowadays been orientated towards Regenerative Medicine and the use of stem cells to repair damaged liver. This review is focused on the available literature concerning the role of stem cells in liver regeneration. It summarizes the results of studies concerning endogenous liver regeneration and stem cell experimental protocols. Moreover, this review discusses the clinical studies that have been conducted in humans so far.
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31
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Utley S, James D, Mavila N, Nguyen MV, Vendryes C, Salisbury SM, Phan J, Wang KS. Fibroblast growth factor signaling regulates the expansion of A6-expressing hepatocytes in association with AKT-dependent β-catenin activation. J Hepatol 2014; 60:1002-9. [PMID: 24365171 PMCID: PMC3995894 DOI: 10.1016/j.jhep.2013.12.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 12/08/2013] [Accepted: 12/10/2013] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Fibroblast Growth Factors (FGFs) promote the proliferation and survival of hepatic progenitor cells (HPCs) via AKT-dependent β-catenin activation. Moreover, the emergence of hepatocytes expressing the HPC marker A6 during 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury is mediated partly by FGF and β-catenin signaling. Herein, we investigate the role of FGF signaling and AKT-mediated β-catenin activation in acute DDC liver injury. METHODS Transgenic mice were fed DDC chow for 14days concurrent with either Fgf10 over-expression or inhibition of FGF signaling via expression of soluble dominant-negative FGF Receptor (R)-2IIIb. RESULTS After 14days of DDC treatment, there was an increase in periportal cells expressing FGFR1, FGFR2, and AKT-activated phospho-Serine 552 (pSer552) β-Catenin in association with up-regulation of genes encoding the FGFR2IIIb ligands, Fgf7, Fgf10, and Fgf22. In response to Fgf10 over-expression, there was an increase in the number of pSer552-β-Catenin((positive)+ive) periportal cells as well as cells co-positive for A6 and hepatocyte marker, Hepatocyte Nuclear Factor-4α (HNF4α). A similar expansion of A6(+ive) cells was observed after Fgf10 over-expression with regular chow and after partial hepatectomy during ethanol toxicity. Inhibition of FGF signaling increased the periportal A6(+ive)HNF4α(+ive) cell population while reducing centrolobular A6(+ive) HNF4α(+ive) cells. AKT inhibition with Wortmannin attenuated FGF10-mediated A6(+ive)HNF4α(+ive) cell expansion. In vitro analyses using FGF10 treated HepG2 cells demonstrated AKT-mediated β-Catenin activation but not enhanced cell migration. CONCLUSIONS During acute DDC treatment, FGF signaling promotes the expansion of A6-expressing liver cells partly via AKT-dependent activation of β-Catenin expansion of A6(+ive) periportal cells and possibly by reprogramming of centrolobular hepatocytes.
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Affiliation(s)
- Sarah Utley
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
,Integrative Biology of Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA
| | - David James
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Nirmala Mavila
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Marie V. Nguyen
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Christopher Vendryes
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - S. Michael Salisbury
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Jennifer Phan
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
| | - Kasper S. Wang
- Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA
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Tsujiwaki M, Murata M, Takasawa A, Hiratsuka Y, Fukuda R, Sugimoto K, Ono Y, Nojima M, Tanaka S, Hirata K, Kojima T, Sawada N. Aberrant expression of claudin-4 and -7 in hepatocytes in the cirrhotic human liver. Med Mol Morphol 2014; 48:33-43. [PMID: 24737165 DOI: 10.1007/s00795-014-0074-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 03/18/2014] [Indexed: 12/16/2022]
Abstract
The liver comprises hepatocytes and non-parenchymal cells such as bile duct epithelial cells. Claudin-4 and -7 are not expressed in hepatocytes under physiological conditions. It was reported that claudin-7 increased in human pulmonary fibroses. We therefore investigated claudin-4 and -7 expressions in human cirrhotic livers, in which hepatocyte proliferation is severely delayed. We examined liver tissues from 50 patients with liver tumors. The expression of claudin-4 and -7 in hepatocytes significantly increased with the grade of fibrosis, not with inflammatory activity, in the liver tissues of chronic hepatitis. The number of claudin-4- and -7-positive cells observed was greater than that of alpha-fetoprotein-positive hepatic progenitor cells. In primary cultures of mouse hepatocytes, the expression of claudin-4 and -7 was not induced by treatment with proinflammatory cytokines. In immunohistochemical analysis of liver tissues of 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated mice and primary cultures of mouse hepatocytes, the expression of claudin-4 and -7 increased with proliferation of progenitor cells. However, the claudin-4- and -7-positive cells were not always progenitor cells. Thus, claudin-4 and -7 were observed in hepatocytes of severely damaged mouse and human livers. These findings suggest that claudin-4- and -7-positive hepatocytes may exist during the process of differentiation from progenitor cells into mature hepatocytes.
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Affiliation(s)
- Mitsuhiro Tsujiwaki
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
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Yin DZ, Cai JY, Zheng QC, Chen ZW, Zhao JX, Yuan YN. Mouse A6-positive hepatic oval cells derived from embryonic stem cells. ACTA ACUST UNITED AC 2014; 34:1-9. [PMID: 24496671 DOI: 10.1007/s11596-014-1223-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Revised: 12/23/2013] [Indexed: 12/14/2022]
Abstract
Oval cells have a potential to differentiate into a variety of cell lineages including hepatocytes and biliary epithelia. Several models have been established to activate the oval cells by incorporating a variety of toxins and carcinogens, alone or combined with surgical treatment. Those models are obviously not suitable for the study on human hepatic oval cells. It is necessary to establish a new and efficient model to study the human hepatic oval cells. In this study, the hepatocyte growth factor (HGF) and epidermal growth factor (EGF) were used to induce differentiation of mouse embryonic stem (ES) cells into hepatic oval cells. We first confirmed that hepatic oval cells derived from ES cells, which are bipotential, do exist during the course of mouse ES cells' differentiation into hepatic parenchymal cells. RT-PCR and transmission electron microscopy were applied in this study. The ratio of Sca-1+/CD34+ cells sorted by FACS in the induction group was increased from day 4 and reached the maximum on the day 8, whereas that in the control group remained at a low level. The differentiation ratio of Sca-1+/CD34+ cells in the induction group was significantly higher than that in the control group. About 92.48% of the sorted Sca-1+/CD34+ cells on the day 8 were A6 positive. Highly purified A6+/Sca-1+/CD34+ hepatic oval cells derived from ES cells could be obtained by FACS. The differentiation ratio of hepatic oval cells in the induction group (up to 4.46%) was significantly higher than that in the control group. The number of hepatic oval cells could be increased significantly by HGF and EGF. The study also examined the ultrastructures of ES-derived hepatic oval cells' membrane surface by atomic force microscopy. The ES-derived hepatic oval cells cultured and sorted by our protocols may be available for the future clinical application.
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Affiliation(s)
- Dong-Zhi Yin
- Department of General Surgery, Huangshi Central Hospital, Huangshi, 435000, China.,Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ji-Ye Cai
- College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
| | - Qi-Chang Zheng
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Zheng-Wei Chen
- Department of Microbiology and Immunology, University of Illinois, College of Medicine, Chicago, IL, 60612, USA
| | - Jing-Xian Zhao
- College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
| | - You-Neng Yuan
- Department of General Surgery, Huangshi Central Hospital, Huangshi, 435000, China
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Abstract
Liver stem/progenitor cells (LPCs) are defined as cells that supply two types of liver epithelial cells, hepatocytes and cholangiocytes, during development, cellular turnover, and regeneration. Hepatoblasts, which are fetal LPCs derived from endoderm stem cells, robustly proliferate and differentiate into hepatocytes and cholangiocytes during fetal life. Between mid-gestation and the neonatal period, some cholangiocytes function as LPCs. Although LPCs in adult livers can be enriched in cells positive for cholangiocyte markers, their tissue localization and functions in cellular turnover remain obscure. On the other hand, it is well known that liver regeneration under conditions suppressing hepatocyte proliferation is supported by LPCs, though their origin has not been clearly identified. Recently many groups took advantage of new techniques including prospective isolation of LPCs by fluorescence-activated cell sorting and genetic lineage tracing to facilitate our understanding of epithelial supply in normal and injured livers. Those works suggest that, in normal livers, the turnover of hepatocytes mostly depends on duplication of hepatocytes. It is also demonstrated that liver epithelial cells as well as LPCs have great plasticity and flexible differentiation capability to respond to various types of injuries by protecting or repairing liver tissues.
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Affiliation(s)
- Naoki Tanimizu
- Department of Tissue Development and Regeneration; Research Institute for Frontier Medicine; Sapporo Medical University School of Medicine; Sapporo, Japan
| | - Toshihiro Mitaka
- Department of Tissue Development and Regeneration; Research Institute for Frontier Medicine; Sapporo Medical University School of Medicine; Sapporo, Japan
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35
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Liu WH, Ren LN, Chen T, You N, Liu LY, Wang T, Yan HT, Luo H, Tang LJ. Unbalanced distribution of materials: the art of giving rise to hepatocytes from liver stem/progenitor cells. J Cell Mol Med 2014; 18:1-14. [PMID: 24286303 PMCID: PMC3916112 DOI: 10.1111/jcmm.12183] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 10/08/2013] [Indexed: 12/12/2022] Open
Abstract
Liver stem/progenitor cells (LSPCs) are able to duplicate themselves and differentiate into each type of cells in the liver, including mature hepatocytes and cholangiocytes. Understanding how to accurately control the hepatic differentiation of LSPCs is a challenge in many fields from preclinical to clinical treatments. This review summarizes the recent advances made to control the hepatic differentiation of LSPCs over the last few decades. The hepatic differentiation of LSPCs is a gradual process consisting of three main steps: initiation, progression and accomplishment. The unbalanced distribution of the affecting materials in each step results in the hepatic maturation of LSPCs. As the innovative and creative works for generating hepatocytes with full functions from LSPCs are gradually accumulated, LSPC therapies will soon be a new choice for treating liver diseases.
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Affiliation(s)
- Wei-Hui Liu
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Li-Na Ren
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Tao Chen
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Nan You
- Department of General Surgery Xinqiao Hospital, Third Military Medical UniversityChongqing, China
| | - Li-Ye Liu
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Tao Wang
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Hong-Tao Yan
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Hao Luo
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
| | - Li-Jun Tang
- General Surgery Center of PLA, Chengdu Military General HospitalChengdu, Sichuan Province, China
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Li J, Xin J, Zhang L, Wu J, Jiang L, Zhou Q, Li J, Guo J, Cao H, Li L. Human hepatic progenitor cells express hematopoietic cell markers CD45 and CD109. Int J Med Sci 2013; 11:65-79. [PMID: 24396288 PMCID: PMC3880993 DOI: 10.7150/ijms.7426] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 12/11/2013] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE To clarify the precise characteristics of human hepatic progenitor cells (HPCs) for future cytotherapy in liver diseases. METHODS Hepatic progenitor-like cells were isolated and cultured from the livers of patients who had undergone partial hepatectomy for various pathologies but displayed no sign of hepatic dysfunction. These cells were characterized by transcriptomic profiling, quantitative real-time PCR and immunocyto/histochemistry. RESULTS Cultured HPCs contained polygonal, high nucleus/cytoplasm ratio and exhibited a global gene expression profile similar (67.8%) to that of primary hepatocytes. Among the genes with more than 20-fold higher expression in HPCs were a progenitor marker (CD90), a pentraxin-related gene (PTX3), collagen proteins (COL5A2, COL1A1 and COL4A2), cytokines (EGF and PDGFD), metabolic enzymes (CYBRD1, BCAT1, TIMP2 and PAM), a secreted protein (SPARC) and an endothelial protein C receptor (PROCR). Moreover, eight markers (ALB, AFP, CK8, CK18, CK19, CD90, CD117 and Oval-6) previously described as HPC markers were validated by qRT-PCR and/or immunocyto/histochemistry. Interestingly, human HPCs were also positive for the hematopoietic cell markers CD45 and CD109. Finally, we characterized the localization of HPCs in the canals of Hering and periportal areas with six previously described markers (Oval-6, CK8, CK18, CK19, CD90 and CD117) and two potential markers (CD45 and CD109). CONCLUSION The human HPCs are highly similar to primary hepatocytes in their transcriptional profiles. The CD45 and CD109 markers could potentially be utilized to identify and isolate HPCs for further cytotherapy of liver diseases.
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Affiliation(s)
- Jun Li
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jiaojiao Xin
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Liyuan Zhang
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jian Wu
- 2. Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Longyan Jiang
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Qian Zhou
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Jun Li
- 3. Department of Pathology, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, China. 310003
| | - Jing Guo
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Hongcui Cao
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
| | - Lanjuan Li
- 1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University. 79 Qingchun Rd., Hangzhou, 310003. China
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Proteins related to early changes in carcinogenesis of hepatic oval cells after treatment with methylnitronitrosoguanidine. ACTA ACUST UNITED AC 2013; 66:139-46. [PMID: 24360059 DOI: 10.1016/j.etp.2013.11.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Revised: 06/19/2013] [Accepted: 11/25/2013] [Indexed: 12/26/2022]
Abstract
Hepatic oval cells are considered as facultative progenitor/stem cells of liver and able to differentiate into either hepatocytes or biliary epithelial cells. The transformed oval cells by carcinogen possess potential to develop carcinomas in animal models. In order to better understand the molecular mechanism in carcinogenetic process, we used a proteomic approach to assess the early changes in protein expression of oval cells (OC3W3-15) initiated by methylnitronitrosoguanidine (MNNG). Meanwhile, we compared cell biologic characteristics of the MNNG treated OC3W3-15 cells and control oval cells by electron microscopy, flow cytometry, karyotype and soft agar assay. The mRNA levels of GGT and GSTP1 determined by real-time PCR were also detected in both cell lines. Our results showed that MNNG-treated OC3W3-15 cells exhibited characteristics of malignant transformation, including growth rate, chromosomal aberrations, abnormal DNA content, and the ability to form colonies. The cells expressed higher levels of the tumor marker AFP, GGT and GSTP1 mRNA than that of control cells. Significant changes of several proteins involved in the malignant transformation process, including cell cycle related proteins, proteins involved in organism development and cell differentiation, are found in OC3W3-15 cells. The proteins may provide early affection in malignant transformation of hepatic oval cells, and yield further insight into mechanism of carcinogenesis of hepatocellular carcinoma.
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Chaudhary K, Liedtke C, Wertenbruch S, Trautwein C, Streetz KL. Caspase 8 differentially controls hepatocytes and non-parenchymal liver cells during chronic cholestatic liver injury in mice. J Hepatol 2013; 59:1292-8. [PMID: 23928400 DOI: 10.1016/j.jhep.2013.07.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 07/14/2013] [Accepted: 07/16/2013] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS Receptor mediated cell death through the activation of caspases has been identified as an important mechanism to control life and death in various tissues and is thus crucial for the maintenance of liver tissue homeostasis. Here we investigated how caspase 8 (Casp8) differentially regulates immune-mediated liver injury and regeneration in distinct liver cell types during chronic liver injury. METHODS Conditional knockout mice with hepatocellular (Casp8(Δhepa)) and ubiquitous deletion of Casp8 (Casp8(ΔMx)) were used in models of cholestatic hepatitis [(DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) treatment, bile duct ligation (BDL) and choline deficient diet with ethionine supplementation (CDE)]. RESULTS Mice with a hepatocellular deletion of Casp8 (Casp8(Δhepa)) were protected after DDC-treatment. Animals with a ubiquitous conditional Casp8 knockout (Casp8(ΔMx)) displayed a significantly enhanced liver injury in various models of cholestatic liver injury. This was associated with higher transaminases, bilirubin levels and finally more liver fibrosis. However, caspase 3 (Casp3) activity was reduced in both knockout strains, suggesting additionally mechanisms contributing to the phenotype. Casp8(ΔMx) mice displayed a stronger infiltration of mononuclear immune cells and more proliferation of liver-parenchymal cells in periportal areas. Further analysis confirmed that these infiltrating immune cells are resistant against extrinsic apoptosis. Bone-marrow-transplantation (BMT) experiments demonstrated that Casp8-deficient bone marrow derived cells are responsible for increased liver injury in DDC fed mice. CONCLUSIONS Our results demonstrate that cell-type specific differences in apoptosis resistance mediated by Casp8 deletion are of significant relevance for the outcome of chronic liver injury.
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Affiliation(s)
- Kunal Chaudhary
- Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany
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Characteristics of hepatic stem/progenitor cells in the fetal and adult liver. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2013; 19:587-93. [PMID: 23010995 DOI: 10.1007/s00534-012-0544-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND The liver is an essential organ that maintains vital activity through its numerous important functions. It has a unique capability of fully regenerating after injury. Regulating a balance between self-renewal and differentiation of hepatic stem cells that are resources for functional mature liver cells is required for maintenance of tissue homeostasis. METHODS This review describes the characteristics of hepatic stem/progenitor cells and the regulatory mechanism of their self-renewal and differentiation capacity. RESULTS In liver organogenesis, undifferentiated hepatic stem/progenitor cells expand their pool by repeated self-renewal in the early stage of liver development and then differentiate into two different types of cell lineage, namely hepatocytes and cholangiocytes. Liver development is regulated by expression of stem cell transcription factors in a complex multistep process. Recent studies suggest that stem cells are maintained by integrative regulation of gene expression patterns related to self-renewal and differentiation by epigenetic mechanisms such as histone modification and DNA methylation. CONCLUSIONS Analysis of the proper regulatory mechanism of hepatic stem/progenitor cells is important for regenerative medicine that utilizes hepatic stem cells and for preventing liver cancer through clarification of the carcinogenetic mechanism involved in stem cell system failure.
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Implication for bone marrow derived stem cells in hepatocyte regeneration after orthotopic liver transplantation. Int J Hepatol 2013; 2013:310612. [PMID: 24109514 PMCID: PMC3784276 DOI: 10.1155/2013/310612] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Revised: 08/05/2013] [Accepted: 08/12/2013] [Indexed: 12/15/2022] Open
Abstract
The liver has the outstanding ability to regenerate itself and restore parenchymal tissue after injury. The most common cell source in liver growth/regeneration is replication of preexisting hepatocytes although liver progenitor cells have been postulated to participate in liver regeneration in cases of massive injury. Bone marrow derived hematopoietic stem cells (BM-HSC) have the formal capacity to act as a source for hepatic regeneration under special circumstances; however, the impact of this process in liver tissue maintenance and regeneration remains controversial. Whether BM-HSC are involved in liver regeneration or not would be of particular interest as the cells have been suggested to be an alternative donor source for the treatment of liver failure. Data from murine models of liver disease show that BM-HSC can repopulate liver tissue and restore liver function; however, data obtained from human liver transplantation show only little evidence for liver regeneration by this mechanism. The cell source for liver regeneration seems to depend on the nature of regeneration process and the extent of injury; however, the precise mechanisms still need to be resolved. Current data suggest, that in human orthotopic liver transplantation, liver regeneration by BM-HSC is a rather rare event and therefore not of clinical relevance.
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Abstract
The liver has an enormous potential to restore the parenchymal tissue loss due to injury. This is accomplished by the proliferation of either the hepatocytes or liver progenitor cells in cases where massive damage prohibits hepatocytes from entering the proliferative response. Under debate is still whether hepatic stem cells are involved in liver tissue maintenance and regeneration or even whether they exist at all. The definition of an adult tissue-resident stem cell comprises basic functional stem cell criteria like the potential of self-renewal, multipotent, i.e. at least bipotent differentiation capacity and serial transplantability featuring the ability of functional tissue repopulation. The relationship between a progenitor and its progeny should exemplify the lineage commitment from the putative stem cell to the differentiated cell. This is mainly assessed by lineage tracing and immunohistochemical identification of markers specific to progenitors and their descendants. Flow cytometry approaches revealed that the liver stem cell population in animals is likely to be heterogeneous giving rise to progeny with different molecular signatures, depending on the stimulus to activate the putative stem cell compartment. The stem cell criteria are met by a variety of cells identified in the fetal and adult liver both under normal and injury conditions. It is the purpose of this review to verify hepatic stem cell candidates in the light of the stem cell definition criteria mentioned. Also from this point of view adult stem cells from non-hepatic tissues such as bone marrow, umbilical cord blood or adipose tissue, have the potential to differentiate into cells featuring functional hepatocyte characteristics. This has great impact because it opens the possibility of generating hepatocyte-like cells from adult stem cells in a sufficient amount and quality for their therapeutical application to treat end-stage liver diseases by stem cell-based hepatocytes in place of whole organ transplantation.
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Affiliation(s)
- Bruno Christ
- Translational Centre for Regenerative Medicine-TRM, University of Leipzig, Philipp-Rosenthal-Straße 55, D-04103 Leipzig, Germany.
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Katz SF, Lechel A, Obenauf AC, Begus-Nahrmann Y, Kraus JM, Hoffmann EM, Duda J, Eshraghi P, Hartmann D, Liss B, Schirmacher P, Kestler HA, Speicher MR, Rudolph KL. Disruption of Trp53 in livers of mice induces formation of carcinomas with bilineal differentiation. Gastroenterology 2012; 142:1229-1239.e3. [PMID: 22342966 DOI: 10.1053/j.gastro.2012.02.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2011] [Revised: 01/20/2012] [Accepted: 02/07/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS p53 limits the self-renewal of stem cells from various tissues. Loss of p53, in combination with other oncogenic events, results in aberrant self-renewal and transformation of progenitor cells. It is not known whether loss of p53 is sufficient to induce tumor formation in liver. METHODS We used AlfpCre mice to create mice with liver-specific disruption of Trp53 (AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice). We analyzed colony formation and genomic features and gene expression patterns in liver cells during hepatocarcinogenesis in mice with homozygous, heterozygous, and no disruption of Trp53. RESULTS Liver-specific disruption of Trp53 consistently induced formation of liver carcinomas that had bilineal differentiation. In nontransformed liver cells and cultured primary liver cells, loss of p53 (but not p21) resulted in chromosomal imbalances and increased clonogenic capacity of liver progenitor cells (LPCs) and hepatocytes. Primary cultures of hepatocytes and LPCs from AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice, but not Cdkn1a(-/-) mice, formed tumors with bilineal differentiation when transplanted into immunocompromised mice. Spontaneous liver tumors that developed in AlfpCre(+)Trp53(Δ2-10/Δ2-10) mice had significant but complex alterations in expression of Rb checkpoint genes compared with chemically induced liver tumors that developed mice with wild-type Trp53. CONCLUSIONS Deletion of p53 from livers of mice is sufficient to induce tumor formation. The tumors have bilineal differentiation and dysregulation of Rb checkpoint genes.
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Affiliation(s)
- Sarah-Fee Katz
- Institute of Molecular Medicine and Max Planck Research Group on Stem Cell Aging, University of Ulm, Ulm, Germany
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Petrenko YA, Petrenko AY. Phenotypical properties and ability to multilineage differentiation of adipose tissue stromal cells during subculturing. CYTOL GENET+ 2012. [DOI: 10.3103/s0095452712010070] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Bin WT, Ma LM, Xu Q, Shi XL. Embryonic hepatocyte transplantation for hepatic cirrhosis: Efficacy and mechanism of action. World J Gastroenterol 2012; 18:309-22. [PMID: 22294837 PMCID: PMC3261526 DOI: 10.3748/wjg.v18.i4.309] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Revised: 07/14/2011] [Accepted: 07/21/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy and mechanism of action of allogeneic embryonic hepatocyte transplantation for the treatment of hepatic cirrhosis.
METHODS: Rat embryonic hepatocytes were characterized by examining cell markers. Wistar rats with CCl4-induced cirrhosis were randomly divided into two groups: a model group receiving continuous CCl4, and a cell transplantation group receiving continuous CCl4 and transplanted with embryonic fluorescent-labeled hepatocytes. In addition, a normal control group was composed of healthy rats. All rats were sacrificed after 2 wk following the initiation of the cell transplant. Ultrasound, pathological analyses and serum biochemical tests were used to evaluate the efficacy of embryonic hepatocyte transplantation. To analyze the recovery status of cirrhotic hepatocytes and the signaling pathways influenced by embryonic hepatocyte transplantation, real-time polymerase chain reaction was performed to examine the mRNA expression of stellate activation-associated protein (STAP), c-myb, α smooth muscle actin (α-SMA) and endothelin-1 (ET-1). Western blotting and immunohistochemistry were employed to detect α-SMA and ET-1 protein expression in hepatic tissues.
RESULTS: Gross morphological, ultrasound and histopathological examinations, serum biochemical tests and radioimmunoassays demonstrated that hepatic cirrhosis was successfully established in the Wistar rats. Stem cell factor receptor (c-kit), hepatocyte growth factor receptor (c-Met), Nestin, α fetal protein, albumin and cytokeratin19 markers were observed in the rat embryonic hepatocytes. Following embryonic hepatocyte transplantation, there was a significant reversal in the gross appearance, ultrasound findings, histopathological properties, and serum biochemical parameters of the rat liver. In addition, after the activation of hepatic stellate cells and STAP signaling, α-SMA, c-myb and ET-1 mRNA levels became significantly lower than in the untreated cirrhotic group (P < 0.05). These levels, however, were not statistically different from those of the normal healthy group. Immunohistochemical staining and Western blot analyses revealed that α-SMA and ET-1 protein expression levels in the transplantation group were significantly lower than in the untreated cirrhotic group, but being not statistically different from the normal group.
CONCLUSION: Transplantation of embryonic hepatocytes in rats has therapeutic effects on cirrhosis. The described treatment may significantly reduce the expression of STAP and ET-1.
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Zhang M, Zhong Y, Chen J. Model systems and clinical applications of hepatic stem cells for liver regeneration. Hepatol Int 2011. [DOI: 10.1007/s12072-011-9323-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Qiu Q, Hernandez JC, Dean AM, Rao PH, Darlington GJ. CD24-positive cells from normal adult mouse liver are hepatocyte progenitor cells. Stem Cells Dev 2011; 20:2177-88. [PMID: 21361791 DOI: 10.1089/scd.2010.0352] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The identification of specific cell surface markers that can be used to isolate liver progenitor cells will greatly facilitate experimentation to determine the role of these cells in liver regeneration and their potential for therapeutic transplantation. Previously, the cell surface marker, CD24, was observed to be expressed on undifferentiated bipotential mouse embryonic liver stem cells and 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced oval cells. Here, we describe the isolation and characterization of a rare, primary, nonhematopoietic, CD24+ progenitor cell population from normal, untreated mouse liver. By immunohistochemistry, CD24-expressing cells in normal adult mouse liver were colocalized with CK19-positive cholangiocytes. This nonhematopoietic (CD45-, Ter119-) CD24+ cell population isolated by flow cytometry represented 0.04% of liver cells and expressed several markers of liver progenitor/oval cells. The immunophenotype of nonhematopoietic CD24+ cells was CD133, Dlk, and Sca-1 high, but c-Kit, Thy-1, and CD34 low. The CD24+ cells had increased expression of CK19, epithelial cell adhesion molecule, Sox 9, and FN14 compared with the unsorted cells. Upon transplantation of nonhematopoietic CD24+ cells under the sub-capsule of the livers of Fah knockout mice, cells differentiated into mature functional hepatocytes. Analysis of X and Y chromosome complements were used to determine whether or not fusion of the engrafted cells with the recipient hepatocytes occurred. No cells were found that contained XXXY or any other combination of donor and host sex chromosomes as would be expected if cell fusion had occurred. These results suggested that CD24 can be used as a cell surface marker for isolation of hepatocyte progenitor cells from normal adult liver that are able to differentiate into hepatocytes.
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Affiliation(s)
- Qiong Qiu
- Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, USA
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Rosenblatt-Velin N, Ogay S, Felley A, Stanford WL, Pedrazzini T. Cardiac dysfunction and impaired compensatory response to pressure overload in mice deficient in stem cell antigen-1. FASEB J 2011; 26:229-39. [PMID: 21957128 DOI: 10.1096/fj.11-189605] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Stem cell antigen-1 (Sca-1) has been used to identify cardiac stem cells in the mouse heart. To investigate the function of Sca-1 in aging and during the cardiac adaptation to stress, we used Sca-1-deficient mice. These mice developed dilated cardiomyopathy [end-diastolic left ventricular diameter at 18 wk of age: wild-type (WT) mice, 4.2 mm ± 0.3; Sca-1-knockout (Sca-1-KO) mice, 4.6 mm ± 0.1; ejection fraction: WT mice, 51.1 ± 2.7%; Sca-1-KO mice, 42.9 ± 2.7%]. Furthermore, the hearts of mice lacking Sca-1 demonstrated exacerbated susceptibility to pressure overload [ejection fraction after transaortic constriction (TAC): WT mice, 43.5 ± 3.2%; Sca-1-KO mice, 30.8% ± 4.0] and increased apoptosis, as shown by the 2.5-fold increase in TUNEL(+) cells in Sca-1-deficient hearts under stress. Sca-1 deficiency affected primarily the nonmyocyte cell fraction. Indeed, the number of Nkx2.5(+) nonmyocyte cells, which represent a population of cardiac precursor cells (CPCs), was 2-fold smaller in Sca-1 deficient neonatal hearts. In vitro, the ability of CPCs to differentiate into cardiomyocytes was not affected by Sca-1 deletion. In contrast, these cells demonstrated unrestricted differentiation into cardiomyocytes. Interestingly, proliferation of cardiac nonmyocyte cells in response to stress, as judged by BrdU incorporation, was higher in mice lacking Sca-1 (percentages of BrdU(+) cells in the heart after TAC: WT mice, 4.4 ± 2.1%; Sca-1-KO mice, 19.3 ± 4.2%). These data demonstrate the crucial role of Sca-1 in the maintenance of cardiac integrity and suggest that Sca-1 restrains spontaneous differentiation in the precursor population. The absence of Sca-1 results in uncontrolled precursor recruitment, exhaustion of the precursor pool, and cardiac dysfunction.
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Teniente-De Alba C, Martínez-Vieyra I, Vivanco-Calixto R, Galván IJ, Cisneros B, Cerecedo D. Distribution of dystrophin- and utrophin-associated protein complexes (DAPC/UAPC) in human hematopoietic stem/progenitor cells. Eur J Haematol 2011; 87:312-22. [PMID: 21623922 DOI: 10.1111/j.1600-0609.2011.01657.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Hematopoietic stem cells (HSC) are defined by their cardinal properties, such as sustained proliferation, multilineage differentiation, and self-renewal, which give rise to a hierarchy of progenitor populations with more restricted potential lineage, ultimately leading to the production of all types of mature blood cells. HSC are anchored by cell adhesion molecules to their specific microenvironment, thus regulating their cell cycle, while cell migration is essentially required for seeding the HSC of the fetal bone marrow (BM) during development as well as in adult BM homeostasis. The dystrophin-associated protein complex (DAPC) is a large group of membrane-associated proteins linking the cytoskeleton to the extracellular matrix and exhibiting scaffolding, adhesion, and signaling roles in muscle and non-muscle cells including mature blood cells. Because adhesion and migration are mechanisms that influence the fate of the HSC, we explored the presence and the feasible role of DAPC. In this study, we characterized the pattern expression by immunoblot technique and, by confocal microscopy analysis, the cellular distribution of dystrophin and utrophin gene products, and the dystrophin-associated proteins (α-, β-dystroglycan, α-syntrophin, α-dystrobrevin) in relation to actin filaments in freshly isolated CD34+ cells from umbilical cord blood. Immunoprecipitation assays demonstrated the presence of Dp71d/Dp71Δ110m ∼DAPC and Up400/Up140∼DAPC. The subcellular distribution of the two DAPC in actin-based structures suggests their dynamic participation in adhesion and cell migration. In addition, the particular protein pattern expression found in hematopoietic stem/progenitor cells might be indicative of their feasible participation during differentiation.
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Affiliation(s)
- Carmen Teniente-De Alba
- Laboratorio de Hematobiología, Escuela Nacional de Medicina y Homeopatía, Instituto Politécnico Nacional (IPN), México, D.F., México
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Li H, Zhang B, Lu Y, Jorgensen M, Petersen B, Song S. Adipose tissue-derived mesenchymal stem cell-based liver gene delivery. J Hepatol 2011; 54:930-8. [PMID: 21168381 PMCID: PMC3079008 DOI: 10.1016/j.jhep.2010.07.051] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Revised: 07/26/2010] [Accepted: 07/28/2010] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The adipose tissue represents an accessible, abundant, and replenishable source of adult stem cells for potential applications in regenerative medicine. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) resemble bone marrow-derived mesenchymal stem cells (BM-MSCs) with respect to morphology, immune-phenotype, and multiple differentiation capability. In the present study, we investigated the feasibility of AT-MSC-based liver gene delivery for the treatment of alpha 1-antitrypsin deficiency. METHODS Mouse AT-MSCs were transduced by rAAV vectors and transplanted into the mouse liver. RESULTS We showed that AT-MSCs can be transduced by recombinant adeno-associated viral vector serotype 1 (rAAV1-CB-hAAT). After transplanting to the mouse liver, ex vivo transduced AT-MSCs expressed the transgene product, human alpha 1-antitrypsin (hAAT). Importantly, serum levels of hAAT were sustained and no anti-hAAT antibody was detected in any recipients. CONCLUSIONS These results demonstrated that AT-MSCs can be transduced by rAAV vectors, engrafted into recipient livers, contribute to liver regeneration, and serve as a platform for transgene expression without eliciting an immune response. AT-MSC-based gene therapy presents a novel approach for the treatment of liver diseases, such as AAT deficiency.
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Affiliation(s)
- Hong Li
- Department of Pharmaceutics, University of Florida, Gainesville, Florida
| | - Bin Zhang
- Department of Pharmaceutics, University of Florida, Gainesville, Florida
| | - Yuanqing Lu
- Department of Pharmaceutics, University of Florida, Gainesville, Florida
| | - Marda Jorgensen
- Brain Institute, University of Florida, Gainesville, Florida
| | - Bryon Petersen
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida
| | - Sihong Song
- Department of Pharmaceutics, University of Florida, Gainesville, Florida
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Shafritz DA, Oertel M. Model systems and experimental conditions that lead to effective repopulation of the liver by transplanted cells. Int J Biochem Cell Biol 2011; 43:198-213. [PMID: 20080205 PMCID: PMC2907475 DOI: 10.1016/j.biocel.2010.01.013] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Revised: 12/22/2009] [Accepted: 01/07/2010] [Indexed: 12/26/2022]
Abstract
In recent years, there has been substantial progress in transplanting cells into the liver with the ultimate goal of restoring liver mass and function in both inherited and acquired liver diseases. The basis for considering that this might be feasible is that the liver is a highly regenerative organ. After massive liver injury or surgical removal of two-thirds or more of the liver tissue, the organ can restore its mass with completely normal morphologic structure and function. It has also been found under highly selective conditions that transplanted hepatocytes can fully repopulate the liver and cure a metabolic disorder or deficiency state. Fetal liver cells can also substantially repopulate the normal liver, and it is hoped in the future that effective repopulation will be achievable with cultured cells or cell lines, pluripotent stem cells from other somatic tissues, embryonic stem cells, or induced pluripotent stem cells, which can now be generated in vitro by a variety of methods. The purpose of this review is to present the major systems that have been used for liver repopulation, the variables involved in obtaining successful repopulation and what has been achieved in these various systems to date with different cell types.
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Affiliation(s)
- David A Shafritz
- Marion Bessin Liver Research Center, Department of Medicine and Division of Hepatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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