Artykuły w czasopismach na temat „Liver cells”
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PD, Gupta. "Liver Cells Can Dedifferentiate and Act as Progenitor Cells for Liver Growth". Journal of Embryology & Stem Cell Research 3, nr 2 (2019): 1–2. http://dx.doi.org/10.23880/jes-16000124.
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Seki, Shuhji, Hiroyuki Nakashima, Masahiro Nakashima i Manabu Kinoshita. "Antitumor Immunity Produced by the Liver Kupffer Cells, NK Cells, NKT Cells, and CD8+CD122+T Cells". Clinical and Developmental Immunology 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/868345.
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Mouse and human livers contain innate immune leukocytes, NK cells, NKT cells, and macrophage-lineage Kupffer cells. Various bacterial components, including Toll-like receptor (TLR) ligands and an NKT cell ligand (α-galactocylceramide), activate liver Kupffer cells, which produce IL-1, IL-6, IL-12, and TNF. IL-12 activates hepatic NK cells and NKT cells to produce IFN-γ, which further activates hepatic T cells, in turn activating phagocytosis and cytokine production by Kupffer cells in a positive feedback loop. These immunological events are essentially evoked to protect the host from bacterial and viral infections; however, these events also contribute to antitumor and antimetastatic immunity in the liver by activated liver NK cells and NKT cells. Bystander CD8+CD122+T cells, and tumor-specific memory CD8+T cells, are also induced in the liver byα-galactocylceramide. Furthermore, adoptive transfer experiments have revealed that activated liver lymphocytes may migrate to other organs to inhibit tumor growth, such as the lungs and kidneys. The immunological mechanism underlying the development of hepatocellular carcinoma in cirrhotic livers in hepatitis C patients and liver innate immunity as a double-edged sword (hepatocyte injury/regeneration, septic shock, autoimmune disease, etc.) are also discussed.
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Wu, Xian, Yongyan Chen, Haiming Wei, Rui Sun i Zhigang Tian. "Development of Murine Hepatic NK Cells during Ontogeny: Comparison with Spleen NK Cells". Clinical and Developmental Immunology 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/759765.
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The phenotype of developing liver NK cells (CD3−NK1.1+) was investigated during mouse ontogeny comparing with spleen NK cells. The highest percentage of hepatic CD27−CD11b−NK cells occurred at the fetal stage. After birth, the percentage of CD27−CD11b−NK cells in both the liver and spleen gradually decreased to their lowest level at 6 weeks. More CD27+CD11b−NK cells were detected in the liver than that in spleen from week 1 to 6. Expression of NKG2A on liver NK cells was decreased but still much higher than that of spleen NK cells after 1 week. The NKG2D expression on liver NK cells increased to its highest level and was significantly higher than on spleen NK cells till 4 weeks. During mouse ontogeny, weaker expression of NKp46 and CD2 and stronger expression of CD69, CD11c, 2B4, and CD73 were observed on liver NK cells. Furthermore, neonatal liver NK cells express higher IFN-γ and perforin than adult .These results suggest that the maturation process of NK cells is unique in the livers, and liver microenvironments might play critical roles to keep NK cells in an immature status.
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Belaschk, Elisa, Susanne Rohn, Ramla Mukiibi, Anja Reutzel-Selke, Peter Tang, Birgit Sawitzki, Johann Pratschke, Igor M. Sauer i Martina T. Mogl. "Isolation, Characterization and Cold Storage of Cells Isolated from Diseased Explanted Livers". International Journal of Artificial Organs 40, nr 6 (23.05.2017): 294–306. http://dx.doi.org/10.5301/ijao.5000594.
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Introduction Livers discarded after standard organ retrieval are commonly used as a cell source for hepatocyte transplantation. Due to the scarcity of organ donors, this leads to a shortage of suitable cells for transplantation. Here, the isolation of liver cells from diseased livers removed during liver transplantation is studied and compared to the isolation of cells from liver specimens obtained during partial liver resection. Methods Hepatocytes from 20 diseased explanted livers (Ex-group) were isolated, cultured and stored at 4°C for up to 48 hours, and compared to hepatocytes isolated from the normal liver tissue of 14 liver lobe resections (Rx-group). The nonparenchymal cell fraction (NPC) was analyzed by flow cytometry to identify potential liver progenitor cells, and OptiPrep™ (Sigma-Aldrich) density gradient centrifugation was used to enrich the progenitor cells for immediate transplantation. Results There were no differences in viability, cell integrity and metabolic activity in cell culture and survival after cold storage when comparing the hepatocytes from the Rx-group and the Ex-group. In some cases, the latter group showed tendencies of increased resistance to isolation and storage procedures. The NPC of the Ex-group livers contained considerably more EpCAM+ and significantly more CD90+ cells than the Rx-group. Progenitor cell enrichment was not sufficient for clinical application. Conclusions Hepatocytes isolated from diseased explanted livers showed the essential characteristics of being adequate for cell transplantation. Increased numbers of liver progenitor cells can be isolated from diseased explanted livers. These results support the feasibility of using diseased explanted livers as a cell source for liver cell transplantation.
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Jauregui, Hugo O., Namita Roy Chowdhury i Jayanta Roy Chowdhury. "Use of Mammalian Liver Cells for Artificial Liver Support". Cell Transplantation 5, nr 3 (maj 1996): 353–67. http://dx.doi.org/10.1177/096368979600500302.
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Advances in orthotopic liver transplantation have improved the survival rate of both acute and chronic liver failure patients to nearly 70%. However, the success of this treatment modality has created an international organ shortage. Many patients die while awaiting transplantation in part due to the minimal capacity to store viable transplantable livers beyond 24 h. Additionally, for many areas of the world, routine use of whole liver transplantation to treat liver disease is impractical due to the demands on both financial and technical resources. Potentially, these issues may be alleviated, at least in part, by the use of liver cell transplantation or cellular-based liver assist devices. The well-documented regenerative capacity of the liver may obviate the need for whole organ transplantation in some instances of acute failure, if the patient may be provided temporary metabolic support. Although other patients ultimately may require transplantation, a longer period of time to find a suitable organ for transplantation may be gained by that supportive therapy. The field of liver cell transplantation may offer solutions to patients with inherited metabolic deficiencies or chronic liver disease. The potential to treat an hepatic disorder by using only a fraction of the whole liver would increase the number of whole organs available for orthotopic liver transplantation. Research in the fields of hepatocyte based intra- and extra-corporeal liver support is providing evidence that these therapeutic modalities may ultimately become routine in the treatment of severe liver disease. A historic overview of that technology along with its current status is discussed.
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Shafritz, David A., Mo R. Ebrahimkhani i Michael Oertel. "Therapeutic Cell Repopulation of the Liver: From Fetal Rat Cells to Synthetic Human Tissues". Cells 12, nr 4 (6.02.2023): 529. http://dx.doi.org/10.3390/cells12040529.
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Progenitor cells isolated from the fetal liver can provide a unique cell source to generate new healthy tissue mass. Almost 20 years ago, it was demonstrated that rat fetal liver cells repopulate the normal host liver environment via a mechanism akin to cell competition. Activin A, which is produced by hepatocytes, was identified as an important player during cell competition. Because of reduced activin receptor expression, highly proliferative fetal liver stem/progenitor cells are resistant to activin A and therefore exhibit a growth advantage compared to hepatocytes. As a result, transplanted fetal liver cells are capable of repopulating normal livers. Important for cell-based therapies, hepatic stem/progenitor cells containing repopulation potential can be separated from fetal hematopoietic cells using the cell surface marker δ-like 1 (Dlk-1). In livers with advanced fibrosis, fetal epithelial stem/progenitor cells differentiate into functional hepatic cells and out-compete injured endogenous hepatocytes, which cause anti-fibrotic effects. Although fetal liver cells efficiently repopulate the liver, they will likely not be used for human cell transplantation. Thus, utilizing the underlying mechanism of repopulation and developed methods to produce similar growth-advantaged cells in vitro, such as human induced pluripotent stem cells (iPSCs). This approach has great translational potential for developing novel cell-based therapies in patients with liver disease. The present review gives a brief overview of the classic cell transplantation models and various cell sources studied as donor cell candidates. The advantages of fetal liver-derived stem/progenitor cells are discussed, as well as the mechanism of liver repopulation. Moreover, this article reviews the potential of in vitro developed synthetic human fetal livers from iPSCs and their therapeutic benefits.
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Jang, Ju Wang, Eric B. Richardson, Sunhoo Park i Seung Bum Lee. "Liver Stem Cells". Hanyang Medical Reviews 34, nr 4 (2014): 145. http://dx.doi.org/10.7599/hmr.2014.34.4.145.
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&NA;. "Sinusoidal Liver Cells". Journal of Pediatric Gastroenterology and Nutrition 4, nr 2 (kwiecień 1985): 335–36. http://dx.doi.org/10.1097/00005176-198504000-00039.
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Matthews, Vance, i George Yeoh. "Liver Stem Cells". IUBMB Life (International Union of Biochemistry and Molecular Biology: Life) 57, nr 8 (1.08.2005): 549–53. http://dx.doi.org/10.1080/15216540500215606.
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Sell, S. "Liver stem cells". Science 260, nr 5112 (28.05.1993): 1224. http://dx.doi.org/10.1126/science.8493561.
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Petrovic, Lydia M. "Regenerating liver cells". Liver Transplantation 7, nr 1 (styczeń 2001): 70–72. http://dx.doi.org/10.1053/jlts.2001.0070070.
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Forbes, Stuart J., i Maurizio Parola. "Liver fibrogenic cells". Best Practice & Research Clinical Gastroenterology 25, nr 2 (kwiecień 2011): 207–17. http://dx.doi.org/10.1016/j.bpg.2011.02.006.
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Lee, Kuei-Chuan, Peng Chen, Igor Maricic, Tatsuo Inamine, Jingjuan Hu, Shenhai Gong, Julia C. Sun i in. "Intestinal iNKT cells migrate to liver and contribute to hepatocyte apoptosis during alcoholic liver disease". American Journal of Physiology-Gastrointestinal and Liver Physiology 316, nr 5 (1.05.2019): G585—G597. http://dx.doi.org/10.1152/ajpgi.00269.2018.
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We investigated the migration of intestinal immune cells to the liver and their contribution to alcoholic liver disease. In mice fed ethanol, we found that an increased number of invariant natural killer T (iNKT) cells, which respond to the antigen presented by CD1d, migrated from mesenteric lymph nodes to the liver. iNKT cells react to lipid antigens, so we studied their activities in mice with intestinal epithelial cell-specific deletion of Pparg ( PpargΔIEC) as a model for altering intestinal lipidomic profiles. Levels of CD1d increased in intestines of ethanol-fed PpargΔIEC mice, and in cell-tracking experiments, more iNKT cells migrated to the liver, compared with mice without disruption of Pparg. Livers of PpargΔIEC mice had increased markers of apoptosis and liver injury after ethanol feeding. iNKT cells isolated from livers of ethanol-fed PpargΔIEC mice induced apoptosis of cultured hepatocytes. An inhibitor of iNKT cells reduced ethanol-induced liver injury in PpargΔIEC mice. Duodenal tissues from patients with alcohol-use disorder have been found to have increased levels of CD1d compared with tissues from patients without alcohol overuse. Ethanol use, therefore, activates iNKT cells in the intestine to migrate to liver, where they—along with the resident hepatic iNKT cells—contribute to hepatocyte death and injury. NEW & NOTEWORTHY In this article, we studied migration of intestinal immune cells into the liver in response to ethanol-induced liver disease. We found that chronic ethanol feeding induces expression of CD1d by enterocytes, which activate invariant natural killer T (iNKT) cells in mesenteric lymph nodes; activation is further increased with loss of peroxisome proliferator-activated receptor gamma gene and altered lipid profiles. The activated iNKT cells migrate into the liver, where they promote hepatocyte apoptosis. Patients with alcohol use disorder have increased expression of CD1d in the small intestine. Strategies to block these processes might be developed to treat alcoholic liver disease.
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Zhou, Ping, Ryan Lahey, Daniel Cortes, Yetunde Olusanya, Sarah Hohm, Ha Tran, David Hess i Jan A. Nolta. "Hepatocyte-Like Cells Can Be Derived from Human Umbilical Cord Blood and Embryonic Stem Cells: Tested in a Novel Mouse Model". Blood 112, nr 11 (16.11.2008): 3490. http://dx.doi.org/10.1182/blood.v112.11.3490.3490.
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Abstract Liver transplantation remains the only therapeutic option for many acute and chronic end-stage liver diseases. However, this approach is limited by a serious shortage of donor organs required for transplantation. Hepatocytes have been reported to be generated from cells not originated from liver, such as hematopoietic stem cells, mesenchymal stem cells and most recently embryonic stem cells. However, the frequency of these stem cell-derived hepatocytes is very low in most studies. Therefore, the significance of stem cell contribution to the repair of liver damage is still controversial. To further explore this potential, we used the beta-glucuronidase (GUSB)-null NOD/SCID/MPSVII mouse model for better identification of engrafted human cells. Enriched cord blood primitive cells (lineage depleted cells with high aldehyde dehydrogenase activity, ALDHhiLin−) were transplanted into irradiated NOD/SCID/MPSVII mice. One month after transplantation, carbon tetrachloride (CCl4) was administrated into the mice twice a week for 4 weeks to induce liver damage. In this model, ALDHhiLin− cells efficiently engrafted in the recipient mouse livers as demonstrated by GUSB positive immunohistological staining and the presence of human Alu DNA using PCR. The percentage of human cells in these livers ranged between 3% and 14.2% using quantitative real-time PCR. These engrafted cells improved recovery of the mice from toxic insult, and significantly increased the numbers of surviving mice. Furthermore, human liver-specific a-1-antitrypsin mRNA and albumin protein were expressed in the recipient livers. Interestingly, human vs. murine centromeric fluorescent in situ hybridization analysis on the liver sections demonstrated that most human cells were not fused to mouse cells. However, mouse nuclei were detected in the majority of the albumin-expressing cells, suggesting that fusion had occurred and was responsible for the appearance of donor derived hepatocyte-like cells. With the goal of achieving higher levels of liver reconstitution than had been possible using the adult stem cells, we began studying engraftment of human embryonic stem cells (hESC), which theoretically have the potential to regenerate any tissue. The H1 cell line was cultured on mouse embryonic fibroblasts then allowed to form embryoid bodies (EBs) in suspension culture for 7 days with or without further expansion and differentiation in attached culture for another month. EBs were dissociated into a single cell suspension and transplanted into NOD/SCID/MPSVII mice or NOD/SCID/IL2Rγ−/− mice via the tail vein after 300 RADs sublethal radiation with or without CCl4 administration. Two months post-transplantation, the human EB-derived cells were found to be well engrafted in the NOD/SCID/MPSVII mouse livers, spleens and kidneys, using the clear-cut enzymatic identification method for cells expressing normal levels of beta-glucuronidase in the mice, which are null for the enzyme. Human DNA was also detected in the recipient mouse liver. Most interestingly, human albumin-expressing cells were also found in the livers of engrafted mice. Our data indicate that the progeny of cord blood stem cells can significantly enhance survival of mice with severe liver damage, and that fusion can occur between transplanted and recipient cells. This could be a normal mechanism of liver repair, since hepatocytes exist normally as multinucleate cells. We also demonstrate that the progeny of hESC can be effectively dissociated and transplanted intravenously, then home to the liver and differentiate to the hepatocyte lineage in an immune deficient mouse model of liver damage.
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Shang, Haitao, Zhijun Wang i Yuhu Song. "Liver progenitor cells-mediated liver regeneration in liver cirrhosis". Hepatology International 10, nr 3 (7.01.2016): 440–47. http://dx.doi.org/10.1007/s12072-015-9693-2.
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Emoto, Masashi, Hans-Willi Mittrücker, Rudolf Schmits, Tak W. Mak i Stefan H. E. Kaufmann. "Critical Role of Leukocyte Function-Associated Antigen-1 in Liver Accumulation of CD4+NKT Cells". Journal of Immunology 162, nr 9 (1.05.1999): 5094–98. http://dx.doi.org/10.4049/jimmunol.162.9.5094.
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Abstract In contrast to peripheral lymphoid organs, a high percentage of T cells in the liver are CD4+NKT cells. We asked whether adhesion molecules play any role in the accumulation of CD4+NKT cells in the liver. Liver CD4+NKT cells expressed ICAM-1 and high levels of LFA-1. In the livers of LFA-1-deficient mice, the number of CD4+NKT cells was markedly decreased. This reduction was restricted to the liver, and no reduction was found in the other organs analyzed. In contrast, the number of liver CD4+NKT cells in ICAM-1-deficient mice was only marginally reduced. In a reciprocal radiation thymocyte reconstitution system with LFA-1-deficient and wild-type mice, LFA-1 expressed on liver cells other than CD4+NKT cells was required for an accumulation of CD4+NKT cells in the liver. These results demonstrate a crucial role for LFA-1 in the accumulation of CD4+NKT cells in the liver.
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Hu, Chenxia, i Lanjuan Li. "In VitroandIn VivoHepatic Differentiation of Adult Somatic Stem Cells and Extraembryonic Stem Cells for Treating End Stage Liver Diseases". Stem Cells International 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/871972.
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The shortage of liver donors is a major handicap that prevents most patients from receiving liver transplantation and places them on a waiting list for donated liver tissue. Then, primary hepatocyte transplantation and bioartificial livers have emerged as two alternative treatments for these often fatal diseases. However, another problem has emerged. Functional hepatocytes for liver regeneration are in short supply, and they will dedifferentiate immediatelyin vitroafter they are isolated from liver tissue. Alternative stem-cell-based therapeutic strategies, including hepatic stem cells (HSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs), are more promising, and more attention has been devoted to these approaches because of the high potency and proliferation ability of the cells. This review will focus on the general characteristics and the progress in hepatic differentiation of adult somatic stem cells and extraembryonic stem cellsin vitroandin vivofor the treatment of end stage liver diseases. The hepatic differentiation of stem cells would offer an ideal and promising source for cell therapy and tissue engineering for treating liver diseases.
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Yu, Qing, Loretta G. Que i Don C. Rockey. "Adenovirus-mediated gene transfer to nonparenchymal cells in normal and injured liver". American Journal of Physiology-Gastrointestinal and Liver Physiology 282, nr 3 (1.03.2002): G565—G572. http://dx.doi.org/10.1152/ajpgi.00512.2000.
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Adenovirus-mediated gene transfer has become an important tool with which to introduce genetic material into cells. Available data emphasize efficient adenoviral transduction of parenchymal liver cells (i.e., hepatocytes) in both in vitro and in vivo model systems, typically in normal cells. The aim of this study was to evaluate gene transfer to nonparenchymal (and parenchymal) cells of the normal and injured rat liver. Hepatocytes, stellate cells, and endothelial cells were isolated by standard methods. Liver injury was induced by bile duct ligation or carbon tetrachloride administration. Cells were transduced in vitro with an adenovirus encoding β-galactosidase (Ad.β-gal) over a range of viral titers, and transduced cells were identified by detection of X-gal. In vivo transduction efficiency was studied in normal and injured livers using cell isolation techniques. Nonparenchymal cells were transduced with greater frequency than hepatocytes at all adenoviral titers tested, both in vitro and in vivo. After liver injury, adenoviral transduction was reduced for all liver cell types compared with that for cells from normal livers (at all virus titers). Notably, transduction efficiency remained greater in nonparenchymal cells than in hepatocytes after liver injury. This work implies that, to achieve comparable gene expression in the injured liver, higher adenoviral titers may be required, an important consideration as gene therapy in disease states is considered.
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Tu, Taojian, Handan Hong, Lina He, Mario Alba, Curtis T. Okamoto i Bangyan L. Stiles. "Abstract 1350: Kupffer cells secrete CXCL5 to promote liver cancer". Cancer Research 83, nr 7_Supplement (4.04.2023): 1350. http://dx.doi.org/10.1158/1538-7445.am2023-1350.
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Abstract Liver carcinoma is the 6th most prevalent cancer worldwide in 2020. Moreover, it is the 3rd leading cause of cancer related deaths. In addition to the genomic and transcriptomic heterogeneity of liver tumor cells which is recognized as a major driver in liver cancer progression, the liver immune system is also fundamental to liver carcinogenesis and presents a promising target for therapy. The liver immune response is orchestrated by cytokines and chemokines. Recent studies suggest that chemokines not only recruit immune cells but also regulate various liver functions. In partial hepatectomy, CXCL2 has been shown to promote hepatocyte proliferation. CXCL1, 2, 5 and 8 can induce endothelial cells chemotaxis to promote angiogenesis through binding to CXCR2. These diverse functions suggest that chemokines could play multifaceted roles in liver cancer development. However, chemokines that are commonly associated with liver cancer is still unknown.We analyzed HCC patient data from the GEO database, and we categorized the datasets based on HCC etiologies including HBV, HCV, alcoholic and NASH. We identified CXCL5 as the only chemokine consistently upregulated in HCC with different etiologies compared to healthy or cirrhotic livers. Immunohistochemistry (IHC) analysis reveals that CXCL5 was produced by immune cells but not tumor cells in human HCC tissues. To further study HCC associated CXCL5 expression, the liver-specific Pten deletion mouse model (PM mice) that recapitulates NAFLD-NASH-HCC progression was used. A gradual increase of hepatic CXCL5 expression is observed during HCC development, reaching nearly 100-fold upregulation of CXCL5 mRNA expression in 12-month-old PM mice livers carrying tumors. Examination of liver immune cell populations showed that macrophages were significantly enriched in Pten deleted livers bearing tumors than wild type livers without tumors. Flow cytometry and IHC analysis further identified Kupffer cells (KCs), the liver resident macrophages as the source of CXCL5 in tumor bearing livers using these mice. Since increased LPS is a prominent feature in most chronic liver diseases, we isolated and treated mouse KCs with LPS and found that LPS treatment robustly increased CXCL5 expression by nearly 20-fold. Interestingly, neither murine macrophage cell lines nor primary peritoneal macrophages displayed induced CXCL5 expression in response to LPS. These data suggest that induction of CXCL5 in KCs is likely a unique function of the KCs but not of other macrophages. To explore the function of CXCL5 in HCC development, we treated mouse hepatocytes and HCC cells with CXCL5 and showed that CXCL5 induces the proliferation of these cells. This effect is further blocked by the inhibition of CXCR2, the receptor of CXCL5, demonstrating the specificity for CXCL5 mediated effects. Together we show here for the first time that CXCL5 expression is a unique property of Kupffer cells and the induction of CXCL5 promotes HCC progression. Citation Format: Taojian Tu, Handan Hong, Lina He, Mario Alba, Curtis T. Okamoto, Bangyan L. Stiles. Kupffer cells secrete CXCL5 to promote liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1350.
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Kung, Janet W. C., Ian S. Currie, Stuart J. Forbes i James A. Ross. "Liver Development, Regeneration, and Carcinogenesis". Journal of Biomedicine and Biotechnology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/984248.
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The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.
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Shafritz, David A., Michael Oertel, Anuradha Menthena, Dirk Nierhoff i Mariana D. Dabeva. "Liver stem cells and prospects for liver reconstitution by transplanted cells". Hepatology 43, S1 (2006): S89—S98. http://dx.doi.org/10.1002/hep.21047.
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Bertolino, Patrick J., Yik Chun Wong, Frederic Sierro, Bo Lu, Szun Szun Tay, Nicole A. W. Wood, Claire McGuffog, Ian E. Alexander, Geoffrey W. McCaughan i David G. Bowen. "Resident memory CD8+ T cells in the liver require presentation by non-parenchymal cells to differentiate". Journal of Immunology 196, nr 1_Supplement (1.05.2016): 64.4. http://dx.doi.org/10.4049/jimmunol.196.supp.64.4.
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Abstract Tissue-resident memory T cells (TRM) have been identified in different organs including skin and lung. Whether TRM can differentiate in the liver is unknown. To induce intrahepatic CD8+ T cell responses, recipient mice were transferred with anti-OVA transgenic T cells and treated with recombinant adeno-associated viral vectors (rAAV) that target mouse hepatocytes to induce de novo OVA expression in the liver. We have recently shown that a low rAAV dose induced a low antigen load and allowed the development of intrahepatic effector T cells. We investigated here whether these cells differentiated into TRM. When 1–5% of hepatocytes expressed OVA, functional memory OVA-specific CD8+ T cells expressing CD69, a common TRM marker, were established in the liver. Intra-vital multi-photon microscopy experiments revealed that these memory cells moved slowly and against the blood flow, suggesting that they were patrolling the hepatic sinusoids. To test the ability of these cells to recirculate, livers containing memory T cells were transplanted into naive recipients. Most donor memory CD8+ T cells were detected within the transplanted livers and very few recirculated into lymphoid tissues, suggesting that they were liver resident. Importantly, when OVA presentation was restricted to hepatocytes, naïve CD8+ T cells became effectors but failed to develop into TRM. In summary, low numbers of antigen-expressing hepatocytes promote the differentiation of liver CD8+ TRM. Although hepatocytes are critical in providing antigen, the differentiation of intrahepatic CD8+ TRM requires non-hepatocyte antigen-presenting cells. Our results have important implications for vaccine development and for the treatment of hepatotropic infections.
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Hyun, Jeongeun, Seh-Hoon Oh, Richard T. Premont, Cynthia D. Guy, Carl L. Berg i Anna Mae Diehl. "Dysregulated activation of fetal liver programme in acute liver failure". Gut 68, nr 6 (22.01.2019): 1076–87. http://dx.doi.org/10.1136/gutjnl-2018-317603.
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ObjectiveUncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3).DesignWe compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury.ResultsLivers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate.ConclusionAfter acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.
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Lombard, Catherine A., Julie Prigent i Etienne M. Sokal. "Human Liver Progenitor Cells for Liver Repair". Cell Medicine 5, nr 1 (marzec 2013): 1–16. http://dx.doi.org/10.3727/215517913x666459.
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DeLeve, Laurie D. "Liver sinusoidal endothelial cells and liver regeneration". Journal of Clinical Investigation 123, nr 5 (1.05.2013): 1861–66. http://dx.doi.org/10.1172/jci66025.
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Ozaki, Michelle K., Yi Zhang, Zheng Xi i Pepper Schedin. "Abstract A046: Liver involution generates a pro-metastatic niche in a murine model of postpartum breast cancer liver metastasis". Cancer Research 84, nr 3_Supplement_1 (1.02.2024): A046. http://dx.doi.org/10.1158/1538-7445.advbc23-a046.
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Abstract Postpartum breast cancer (PPBC), cases diagnosed within 10 years of childbirth, has increased risk of liver metastases. Our lab has shown that the liver undergoes growth during pregnancy and lactation to support milk production, and upon weaning, undergoes involution. We have previously shown the actively involuting liver supports breast cancer liver metastasis in rodent models of PPBC, yet the mechanisms are poorly understood. Here, we performed RNAseq analysis in mouse livers across a lactation/wean cycle, and identify stromal alterations that may contribute to the “involution-educated” metastatic niche. During involution, RNA seq analysis reveals increased signatures for apoptotic cell death, catabolic metabolism, regulatory immune cell abundance, and extracellular matrix remodeling consistent with fibroblast activation. Using liver perfusion methods in live animals, we isolated viable stromal cells from livers of nullip or involution mice and validated these cells as highly enriched for fibroblasts by quantitative PCR. Liver fibroblasts were then mixed 1:1 with mouse mammary tumor cells, and injected into host mice at the flank site. We found fibroblasts from involuting livers generated larger tumors (n=28 tumors/group p=0.013), with decreased caspase 3 staining. Further, involution fibroblast tumors had increased ECM deposition as measured by trichrome staining, consistent with involution liver fibroblasts being more activated. Combined these data suggest that involution liver fibroblasts support tumor growth by suppressing tumor cell death, and by providing a pro-tumor collagen matrix when compared to nulliparous liver fibroblasts. These data implicate fibroblasts as components of the involution-educated metastatic niche in the postpartum liver. RNAseq analysis of involuting livers also identified gene signatures correlated with immature myeloid cells that associate with immune suppression and worse prognosis in numerous cancers. We thus evaluated for immature myeloid cells by multiplex immunohistochemistry in healthy mouse livers across a reproductive cycle, and identified increased abundance of immature myeloid cells (CD45+, CD11b+, Gr-1+) specifically during involution (n=6/group, p<0.05). Further, our data suggest liver involution may have a durable impact on immune composition of breast cancer liver metastases, as we find evidence for increased immature myeloid cells (CD45+, CD11b+, CD33+, CD68-, CD66b-, Cd56-, CD11c-, CD20-) in liver metastases of PPBC patients compared to non-PPBC patients. These data implicate immature myeloid cells as another component of the involution-educated liver metastatic niche. In sum, we find physiological involution of the liver post-wean alters the liver stromal microenvironment in a manner consistent with establishing a metastatic niche. Our findings may lead to the identification of liver stromal targets that can be exploited for prevention and or treatment strategies for PPBC liver metastasis. Citation Format: Michelle K Ozaki, Yi Zhang, Zheng Xi, Pepper Schedin. Liver involution generates a pro-metastatic niche in a murine model of postpartum breast cancer liver metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A046.
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Österreicher, Christoph H., Melitta Penz-Österreicher, Sergei I. Grivennikov, Monica Guma, Ekaterina K. Koltsova, Christian Datz, Roman Sasik, Gary Hardiman, Michael Karin i David A. Brenner. "Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver". Proceedings of the National Academy of Sciences 108, nr 1 (20.12.2010): 308–13. http://dx.doi.org/10.1073/pnas.1017547108.
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Cirrhosis is the end result of chronic liver disease. Hepatic stellate cells (HSC) are believed to be the major source of collagen-producing myofibroblasts in cirrhotic livers. Portal fibroblasts, bone marrow-derived cells, and epithelial to mesenchymal transition (EMT) might also contribute to the myofibroblast population in damaged livers. Fibroblast-specific protein 1 (FSP1, also called S100A4) is considered a marker of fibroblasts in different organs undergoing tissue remodeling and is used to identify fibroblasts derived from EMT in several organs including the liver. The aim of this study was to characterize FSP1-positive cells in human and experimental liver disease. FSP1-positive cells were increased in human and mouse experimental liver injury including liver cancer. However, FSP1 was not expressed by HSC or type I collagen-producing fibroblasts. Likewise, FSP1-positive cells did not express classical myofibroblast markers, including αSMA and desmin, and were not myofibroblast precursors in injured livers as evaluated by genetic lineage tracing experiments. Surprisingly, FSP1-positive cells expressed F4/80 and other markers of the myeloid-monocytic lineage as evaluated by double immunofluorescence staining, cell fate tracking, flow cytometry, and transcriptional profiling. Similar results were obtained for bone marrow-derived and peritoneal macrophages. FSP1-positive cells were characterized by increased expression of COX2, osteopontin, inflammatory cytokines, and chemokines but reduced expression of MMP3 and TIMP3 compared with Kupffer cells/macrophages. These findings suggest that FSP1 is a marker of a specific subset of inflammatory macrophages in liver injury, fibrosis, and cancer.
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Eckert, Christoph, Yong Ook Kim, Henrike Julich, Eva-Carina Heier, Niklas Klein, Elmar Krause, Thomas Tschernig i in. "Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver". American Journal of Physiology-Gastrointestinal and Liver Physiology 310, nr 1 (1.01.2016): G1—G12. http://dx.doi.org/10.1152/ajpgi.00344.2015.
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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 (gp38hiCD133−, gp38lowCD133−, 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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Mitaka, Toshihiro, Norihisa Ichinohe i Naoki Tanimizu. "“Small Hepatocytes” in the Liver". Cells 12, nr 23 (27.11.2023): 2718. http://dx.doi.org/10.3390/cells12232718.
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Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), which possess a limited proliferative capability; and type III cells (MH-III), which lose the ability to divide (replicative senescence) and reach the final differentiated state. These subpopulations may explain the liver’s development and growth after birth. Generally, small-sized hepatocytes emerge in mammal livers. The cells are characterized by being morphologically identical to hepatocytes except for their size, which is substantially smaller than that of ordinary MHs. We initially discovered small hepatocytes (SHs) in the primary culture of rat hepatocytes. We believe that SHs are derived from MH-I and play a role as hepatocytic progenitors to supply MHs. The population of MH-I (SHs) is distributed in the whole lobules, a part of which possesses a self-renewal capability, and decreases with age. Conversely, injured livers of experimental models and clinical cases showed the emergence of SHs. Studies demonstrate the involvement of SHs in liver regeneration. SHs that appeared in the injured livers are not a pure population but a mixture of two distinct origins, MH-derived and hepatic-stem-cell-derived cells. The predominant cell-derived SHs depend on the proliferative capability of the remaining MHs after the injury. This review will focus on the SHs that appeared in the liver and discuss the significance of SHs in liver regeneration.
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Ebrahim, Nesrine, Omnia A. M. Badr, Mohamed M. Yousef, Amira Hassouna, Dina Sabry, Ayman Samir Farid, Ola Mostafa i in. "Functional Recellularization of Acellular Rat Liver Scaffold by Induced Pluripotent Stem Cells: Molecular Evidence for Wnt/B-Catenin Upregulation". Cells 10, nr 11 (20.10.2021): 2819. http://dx.doi.org/10.3390/cells10112819.
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Background. Liver transplantation remains the only viable therapy for liver failure but has a severely restricted utility. Here, we aimed to decellularize rat livers to form acellular 3D bio-scaffolds suitable for seeding with induced pluripotent cells (iPSCs) as a tool to investigate the role of Wnt/β-catenin signaling in liver development and generation. Methods. Dissected rat livers were randomly divided into three groups: I (control); II (decellularized scaffolds) and III (recellularized scaffolds). Liver decellularization was established via an adapted perfusion procedure and assessed through the measurement of extracellular matrix (ECM) proteins and DNA content. Liver recellularization was assessed through histological examination and measurement of transcript levels of Wnt/β-catenin pathway, hepatogenesis, liver-specific microRNAs and growth factors essential for liver development. Adult rat liver decellularization was confirmed by the maintenance of ECM proteins and persistence of growth factors essential for liver regeneration. Results. iPSCs seeded rat decellularized livers displayed upregulated transcript expression of Wnt/β-catenin pathway-related, growth factors, and liver specification genes. Further, recellularized livers displayed restored liver-specific functions including albumin secretion and urea synthesis. Conclusion. This establishes proof-of-principle for the generation of three-dimensional liver organ scaffolds as grafts and functional re-establishment.
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Sell, Stewart, i Hyam L. Leffert. "Liver Cancer Stem Cells". Journal of Clinical Oncology 26, nr 17 (10.06.2008): 2800–2805. http://dx.doi.org/10.1200/jco.2007.15.5945.
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In an effort to review the evidence that liver cancer stem cells exist, two fundamental questions must be addressed. First, do hepatocellular carcinomas (HCC) arise from liver stem cells? Second, do HCCs contain cells that possess properties of cancer stem cells? For many years the finding of preneoplastic nodules in the liver during experimental induction of HCCs by chemicals was interpreted to support the hypothesis that HCC arose by dedifferentiation of mature liver cells. More recently, recognition of the role of small oval cells in the carcinogenic process led to a new hypothesis that HCC arises by maturation arrest of liver stem cells. Analysis of the cells in HCC supports the presence of cells with stem-cell properties (ie, immortality, transplantability, and resistance to therapy). However, definitive markers for these putative cancer stem cells have not yet been found and a liver cancer stem cell has not been isolated.
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Mergental, Hynek, Darius Mirza, Simon Afford i Ricky Bhogal. "The Emerging Importance of Liver Sinusoidal Endothelial Cells in Regulating Injury during Machine Perfusion of Deceased Liver Donors". Seminars in Liver Disease 38, nr 03 (24.07.2018): 252–59. http://dx.doi.org/10.1055/s-0038-1661371.
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AbstractWhile majority of liver transplants worldwide continue to be performed using deceased donor organs, the demands for donor livers continues to exceed the current supply. In an attempt to maximize the number of potentially usable donor livers and expand the current donor pool, there is intense global research by various groups exploring the role of machine perfusion in the liver transplantation, particularly with respect to the machine perfusion of extended-criteria liver donors. In this review, the authors summarize the current field of machine perfusion strategies as applied to deceased donor liver transplantation and how therapeutic targeting of the liver sinusoidal endothelial cell may improve the quality of donor livers.
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Shagidulin, M. Yu, N. A. Onishchenko, M. E. Krasheninnikov, A. O. Nikolskaya, E. A. Volkova, I. M. Iljinsky, N. P. Mogeiko, V. I. Sevastianov i S. V. Gautier. "The influence of the ratio of liver cells and bone marrow in the implantable cell-engineering structures of the liver on the recovery efficiency of functional and morphological parameters in chronic liver failure". Russian Journal of Transplantology and Artificial Organs 21, nr 1 (18.05.2019): 122–34. http://dx.doi.org/10.15825/1995-1191-2019-1-122-134.
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Aim: to determinate the most effective liver cells and multipotent mesenchymal stromal cells of bone marrow (MMSC BM) ratio into implantable cell engineering constructions (CECs) used for chronic liver failure (CLF) correcting.Materials and methods. For creating liver CECs it was used a biopolymer implant – a composition of a heterogeneous collagen-containing gel (BMCG) (Sphero®GEL trademark) containing viable liver cells and MMSC BM in the following ratios – 1 : 1; 5 : 1 and 10 : 1 respectively. CECs with different ratios of liver cells and MMSC BM were implanted into liver of rats in which chronic liver failure (CLF), was modeled by using CCl4. The effectiveness of the regulatory effects of CECs (with different cell ratios) on regenerative processes in livers were assessed by using biochemical, morphological and morphometric methods at different periods after their implantation.Results. Corrective effect of CECs with different cell composition on biochemical and morphological parameters of livers at chronic liver failure was established. During studying the liver CECs with various cell ratios of liver cells and MMSC BM (1 : 1; 5 : 1 and 10 : 1 respectively), it was found that the most optimal ratio of cells into the CECs is 5 : 1, because at this ratio of cells, there were a more distinct normalization of the morphological and functional liver parameters within 365 days after modeling CLF and maintenance of the structural homeostasis into the CECs. Themselves, which allows predicting their long-term regulatory effect on the liver tissue in CLF and maintaining its normal structural and functional state.Conclusion. The effective correction of chronic liver failure can be carried out by using the implanted liver CECs, in which donor liver cells and MMSC BM where presented in ratios – 1 : 1; 5 : 1 and 10 : 1. But analysis of prolonged correction of liver morphological and functional parameters at CECs using it was allow to recommend the preferences using of CECs with ratio 5 : 1, because prolonged preservation of structural homeostasis into these CECs makes possible to prognosticate their prolonged regulatory action on the liver tissue at CLF, especially for recipients on a waiting list for liver transplantation.
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Malone, Frances R., Weigang Wang, Zihui Meng, Jorge D. Reyes i Wei Li. "Inverse relationship between liver γδT cells and Foxp3+CD25+CD4+ Tregs contributes to liver allograft tolerance and rejection (141.44)". Journal of Immunology 182, nr 1_Supplement (1.04.2009): 141.44. http://dx.doi.org/10.4049/jimmunol.182.supp.141.44.
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Abstract Our previous studies have demonstrated that Foxp3+CD25+CD4+ regulatory T (Treg) cells play an important role in inducing liver transplant tolerance. It is unknown whether γdT cells are involved in liver tolerance and how they interact with other types of cells. In this study, we examined the involvement of γdT cells in liver transplant tolerance by using an orthotopic liver transplantation model in which liver allografts are accepted spontaneously across the MHC barrier. Controls received either anti-CTLA4 mAb or anti-CD25 mAb pre- or peri-operatively, which induced acute liver allograft rejection. The majority of γdT cells were located in the liver and were CD4 and CD8 negative, did not express TCRαβ and NK receptors. In contrast to Foxp3+CD4+CD25+ Treg, γdT cells were decreased in the spontaneously tolerant liver allografts throughout the time courses from day 1 to day 100 posttransplantation and increased in the rejected liver grafts at day 5 posttransplantation. The CD4 and CD8 marker expression on γdT cells were increased in the tolerated livers post transplantation (10-20%). We speculate that the decreased number of γdT cells in the tolerated liver allografts may be due to the suppressive effect of Foxp3+CD4+CD25+ Treg. Therefore, γδ T cells, expressed in opposite frequency to Foxp3+CD4+CD25+ Treg, are involved in the processes of liver transplant tolerance.
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Ribera, Jordi, Montse Pauta, Pedro Melgar-Lesmes, Bernat Córdoba, Anna Bosch, Maria Calvo, Daniel Rodrigo-Torres i in. "A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury". American Journal of Physiology-Gastrointestinal and Liver Physiology 313, nr 5 (1.11.2017): G492—G504. http://dx.doi.org/10.1152/ajpgi.00428.2016.
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Rising evidence points to endothelial-to-mesenchymal transition (EndMT) as a significant source of the mesenchymal cell population in fibrotic diseases. In this context, we hypothesized that liver endothelial cells undergo EndMT during fibrosis progression. Cirrhosis in mice was induced by CCl4. A transgenic mouse expressing a red fluorescent protein reporter under the control of Tie2 promoter (Tie2-tdTomato) was used to trace the acquisition of EndMT. Sinusoidal vascular connectivity was evaluated by intravital microscopy and high-resolution three-dimensional confocal microscopy. A modest but significant fraction of liver endothelial cells from both cirrhotic patients and CCl4-treated Tie2-tdTomato mice acquired an EndMT phenotype characterized by the coexpression of CD31 and α-smooth muscle actin, compared with noncirrhotic livers. Bone morphogenetic protein-7 (BMP-7) inhibited the acquisition of EndMT induced by transforming growth factor-β1 (TGF-β1) treatment in cultured primary mouse liver endothelial cells from control mice. EndMT was also reduced significantly in vivo in cirrhotic Tie2-tdTomato mice treated intraperitoneally with BMP-7 compared with untreated mice (1.9 ± 0.2 vs. 3.8 ± 0.3%, respectively; P < 0.05). The decrease of EndMT in cirrhotic livers correlated with a significant decrease in liver fibrosis ( P < 0.05) and an improvement in the vascular disorganization rate ( P < 0.05). We demonstrated the acquisition of the EndMT phenotype by a subpopulation of endothelial cells from cirrhotic livers in both animal models and patients. BMP-7 treatment decreases the occurrence of the EndMT phenotype and has a positive impact on the severity of disease by reducing fibrosis and sinusoidal vascular disorganization. NEW & NOTEWORTHY A subpopulation of liver endothelial cells from cirrhotic patients and mice with liver fibrosis undergoes endothelial-to-mesenchymal transition. Liver endothelial cells from healthy mice could transition into a mesenchymal phenotype in culture in response to TGF-β1 treatment. Fibrotic livers treated chronically with BMP-7 showed lower EndMT acquisition, reduced fibrosis, and improved vascular organization.
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Diehl, Anna Mae. "Recent Events in Alcoholic Liver Disease V. Effects of ethanol on liver regeneration". American Journal of Physiology-Gastrointestinal and Liver Physiology 288, nr 1 (styczeń 2005): G1—G6. http://dx.doi.org/10.1152/ajpgi.00376.2004.
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Liver regeneration is necessary to recover from alcoholic liver injury. Herein, we review evidence that ethanol interferes with liver regeneration. Briefly, alcoholic fatty livers demonstrate increased rates of hepatocyte death. The latter provides a regenerative stimulus. However, unlike mature hepatocytes in healthy adult livers, most surviving mature hepatocytes in alcoholic fatty livers cannot replicate. Therefore, less mature cells (progenitors) must differentiate to replace dead hepatocytes. Little is known about the general mechanisms that modulate the differentiation of liver progenitors in adults. Delineation of these mechanisms and clarification of how ethanol influences them might suggest new therapies for alcoholic liver disease.
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Mikhail, Sameh, i Aiwu Ruth He. "Liver Cancer Stem Cells". International Journal of Hepatology 2011 (2011): 1–5. http://dx.doi.org/10.4061/2011/486954.
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Hepatocellular carcinoma is the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related death. Recent research supports that liver cancer is a disease of adult stem cells. From the models of experimental hepatocarcinogenesis, there may be at least three distinct cell lineages with progenitor properties susceptible to neoplastic transformation. Identification of specific cell surface markers for each of the liver cell types, production of corresponding monoclonal antibodies and cell sorting techniques have together revolutionized the characteristics of normal stem cells. In hepatocarcinogenesis, multiple signaling transduction pathways, important for stem cell proliferation and differentiations, are deregulated. Strategies are being developed to identify and characterize the liver cancer stem cells. Targeting liver cancer stem cells may bring hope to curing hepatocellular carcinoma.
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Ramadori, Giuliano, i Karl H. Meyer zum Büschenfelde. "Liver cells and cytokines". Current Opinion in Gastroenterology 9, nr 3 (maj 1993): 359–66. http://dx.doi.org/10.1097/00001574-199305000-00005.
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Ramadori, Giuliano, i Karl H. Meyer zum Büschenfelde. "Liver cells and cytokines". Current Opinion in Gastroenterology 9, nr 3 (maj 1993): 359–66. http://dx.doi.org/10.1097/00001574-199309030-00005.
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Fausto, Nelson. "Tweaking liver progenitor cells". Nature Medicine 11, nr 10 (październik 2005): 1053–54. http://dx.doi.org/10.1038/nm1005-1053.
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Crispe, Ian Nicholas. "Liver antigen-presenting cells". Journal of Hepatology 54, nr 2 (luty 2011): 357–65. http://dx.doi.org/10.1016/j.jhep.2010.10.005.
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熊, 凌风. "Inflammatory Microenvironment: Problems of Liver Tumor Cells and Liver Cancer Stem Cells". Advances in Clinical Medicine 11, nr 10 (2021): 4591–603. http://dx.doi.org/10.12677/acm.2021.1110675.
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Yassin, Abdallah, Bastian Höchst i Percy A. Knolle. "SAT-382-Crosstalk between liver NKT cells and liver sinusoidal endothelial cells". Journal of Hepatology 70, nr 1 (kwiecień 2019): e803. http://dx.doi.org/10.1016/s0618-8278(19)31602-0.
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Nguyen, Hoang Minh Lawrence, T. Peter Kingham, George Plitas, Bryan M. Burt, Umer I. Chaudhry i Ronald P. DeMatteo. "Liver plasmacytoid dendritic cells stimulate NK1.1+ cells (82.12)". Journal of Immunology 178, nr 1_Supplement (1.04.2007): S111. http://dx.doi.org/10.4049/jimmunol.178.supp.82.12.
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Abstract Introduction: Plasmacytoid dendritic cells (pDC) play a central role in innate immunity. While much is known about spleen pDC, liver pDC has only been recently identified and their function remains largely unknown. We sought to determine the ability of liver pDC to stimulate NK1.1+ cells in vitro in comparison to spleen pDC. Methods: Liver and spleen pDC (CD11c+B220+NK1.1−CD19−CD11b−) from C57BL/6 mice were expanded in vivo with an adenovirus encoding murine Flt3L cDNA and isolated by fluorescence activated cell sorting. These cells were co-cultured with spleen NK1.1+ cells in the presence of CpG with or without a transwell insert. After 24 hours, supernatant IFN-γ level was determined by cytometric bead array. Additionally, α-GalCer –loaded liver and spleen pDC were stimulated with CpG and cultured with spleen NK1.1+ cells in the presence of CpG. IFN-γ production was measured after 24 hours. Results: Flt3L-expanded liver pDC stimulated with CpG induced significantly higher CD69 expression on NK cells when compared to spleen pDC. CD69 expression by both groups was reduced by the presence of a transwell insert. Both liver and spleen pDC loaded with α-GalCer and stimulated with CpG induced large amounts of IFN-γ secretion by NK cells. Conclusion: Upon expansion and stimulation, liver pDC are able to stimulate NK cells in vitro. This is partially mediated through cell-cell contact. This work was supported by grant DK068346
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Gandhi, Armin Aabish, Filipe Araujo Hoffmann, Michael LaPorte II, Aaron Havas, Adarsh Rajesh, Andrew Davis, Marcos G. Teneche, Jessica Proulx, Susan Kaech i Peter D. Adams. "Abstract 1407: Investigating the effect of an aged liver microenvironment on immune surveillance and predisposition to cancer". Cancer Research 84, nr 6_Supplement (22.03.2024): 1407. http://dx.doi.org/10.1158/1538-7445.am2024-1407.
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Abstract The incidence of liver cancer is increasing and there is an urgent need for new therapies and preventative strategies. Age is a major risk factor for liver cancer, the reasons for which are not well defined. One of the hallmarks of aging is immune dysfunction which affects liver homeostasis potentially making it prone to cancer. To understand the role of immune dysfunction in aging liver, we analyzed immune cells from young and old livers. As is reported before, in aged livers we observed an increase in CD101+PD1+CD8+ T cell population as well as an increase in an IFNγ+TNFα+ population suggesting an increase in T cell response in an aging liver. We next sought to understand the cause of T cell exhaustion in aged livers. Cell cluster analysis of the young (4-month-old) and old (22 month old) livers by scRNA seq revealed a cell population unique to the aged livers, showing increased expression of immune checkpoint ligands as well as tumor-initiating cell markers. We validated this data by flow cytometry. We next functionally probed the immune environment of aged liver, by testing the effect of cognate antigen expression in young and old hepatocytes on adoptively transferred activated P14 CD8+ T cells isolated from a young P14 mouse. Analysis of the ex vivo activated P14 CD8+ T cells from young and old antigen-expressing livers by flow cytometry and scRNA sequencing revealed increased exhaustion and cytokine-deficiency in old mice as compared to the young mice. This study explores the age-associated alterations in the immune cells in the liver, aiming to alter liver-resident immune cells and their metabolic states in a way that promotes anti-tumor immunity in an aging liver. Citation Format: Armin Aabish Gandhi, Filipe Araujo Hoffmann, Michael LaPorte II, Aaron Havas, Adarsh Rajesh, Andrew Davis, Marcos G. Teneche, Jessica Proulx, Susan Kaech, Peter D. Adams. Investigating the effect of an aged liver microenvironment on immune surveillance and predisposition to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1407.
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Najimi, Mustapha, Dung Ngoc Khuu, Philippe Antoine Lysy, Nawal Jazouli, Jorge Abarca, Christine Sempoux i Etienne Marc Sokal. "Adult-Derived Human Liver Mesenchymal-Like Cells as a Potential Progenitor Reservoir of Hepatocytes?" Cell Transplantation 16, nr 7 (sierpień 2007): 717–28. http://dx.doi.org/10.3727/000000007783465154.
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It is currently accepted that adult tissues may develop and maintain their own stem cell pools. Because of their higher safety profile, adult stem cells may represent an ideal candidate cell source to be used for liver cell therapies. We therefore evaluated the differentiation potential of mesenchymal-like cells isolated from adult human livers. Mesenchymal-like cells were isolated from enzymatically digested adult human liver and expanded in vitro. Cell characterization was performed using flow cytometry, RT-PCR, and immunofluorescence, whereas the differentiation potential was evaluated both in vitro after incubation with specific media and in vivo after intrasplenic transplantation of uPA+/+-SCID and SCID mice. Adult-derived human liver mesenchymal-like cells expressed both hepatic and mesenchymal markers among which albumin, CYP3A4, vimentin, and α-smooth muscle actin. In vitro differentiation studies demonstrated that these mesenchymal-like cells are preferentially determined to differentiate into hepatocyte-like cells. Ten weeks following intrasplenic transplantation into uPA+/+-SCID mice, recipient livers showed the presence of human hepatocytic cell nodules positive for human albumin, prealbumin, and α-fetoprotein. In SCID transplanted liver mice, human hepatocyte-like cells were mostly found near vascular structures 56 days posttransplantation. In conclusion, the ability of isolated adult-derived liver mesenchymal stem-like cells to proliferate and differentiate into hepatocyte-like cells both in vitro and in vivo leads to propose them as an attractive expandable cell source for stem cell therapy in human liver diseases.
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Ding, Chencheng, Yunjie Zheng, Dan Li, Min Zhu i Yong Zhu. "Up-Regulation of miR-1925 by Bone Marrow Mesenchymal Stem Cell (BMSC) Inhibits the Growth of Liver Cancer by Promoting the Anti-Tumor Activity of Natural Killer (NK) Cells". Journal of Biomaterials and Tissue Engineering 12, nr 3 (1.03.2022): 630–33. http://dx.doi.org/10.1166/jbt.2022.2920.
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Hepatocellular carcinoma (HCC) seriously threatens human health and life quality. Natural killer (NK) cells play important roles in liver immune function. Bone marrow mesenchymal stem cell (BMSC) exosomes (Exo) participate in tissue damage. This study explored BMSC-Exo’s effect on NK cells’ anti-tumor activity. NK cells were isolated from the livers of mice with liver cancer. NK cells with or without BMSC-Exo treatment were co-cultured with liver cancer cells to assess cell proliferation. Administration of BMSC-Exo into mice with liver cancer significantly suppressed liver cancer cell growth. In addition, BMSC-Exo treatment significantly improved NK cells’ anti-tumor effect whic was related to BMSC-Exo-induced up-regulation of miR-1925. Implantation of BMSC-Exo into mice with liver cancer at different time periods can significantly suppress liver cancer cell growth. At the same time, BMSC-Exo implantation inhibited the expression of cell proliferation marker protein(Ki67). In vitro study found that BMSC-Exo treatment significantly increased miR-1925 level and the toxicity of NK cells to HCC cells. In addition, miR-1925 overexpression in NK cells significantly increased NK cells’ anti-tumor activity. In conclusion, this study proved that up-regulation of miR-1925 by BMSC can inhibit the growth of liver cancer by promoting the anti-tumor activity of NK cells.
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Zhou, Ping, Sara Hohm, David A. Hess i Jan A. Nolta. "Liver Engraftment by Transplanted Human Progenitor Cells with High Aldehyde Dehydrogenase Activity in a Novel Model, NOD/SCID/MPSVII Mice." Blood 110, nr 11 (16.11.2007): 434. http://dx.doi.org/10.1182/blood.v110.11.434.434.
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Abstract Hematopoietic stem cells (HSC) have been reported to generate cells other than the blood lineage and thus hold enormous promise for repairing damaged tissues. Evidence from our lab and others suggests that hepatocytes can be derived from HSC. However, the frequency of HSC-derived hepatocytes varies tremendously among various studies which use different stem cell subsets and different mouse models. Therefore, the significance of hematopoietic stem cell contribution to the repair of liver damage is still controversial. To further explore this potential, we used the beta-glucuronidase (GUSB)-deficient NOD/SCID/MPSVII mouse model for better identification of engrafted human cells. We and others have previously shown that lineage depleted (lin−) human umbilical cord blood-derived cells with high aldehyde dehydrogenase activity (ALDHhi) are enriched for primitive HSC. In the current studies, ALDHhi lin− cells were transplanted into irradiated NOD/SCID/MPSVII mice. One month after transplantation, carbon tetrachloride (CCl4) was administrated into the mice twice a week for 4 weeks to induced liver damage. In this model, ALDHhi lin− cells gave rise to robust hematopoietic reconstitution (71%±13.1 in bone marrow, 12.8%±4% in peripheral blood and 10.7%±8.8% in spleen) while ALDHlolin− cells failed to engraft. In the liver, engraftment of human cells in mice tansplanted with ALDHhi lin− cells was demonstrated by the presence of human Alu DNA using PCR. CD45+ cells were detected by both FACS (2.11%±1.1) and by immunohistological staining in the liver sections. GUSB expression was frequently evident in kuffer cells adjacent to blood vessels and to a lesser extent in the liver parenchyma. GUSB+ cells were more abundant than CD45+ cells. Most interestingly, human liver-specific a-1-antitrypsin mRNA was detected in the recipient murine livers by RT-PCR analysis. Human albumin- expressing cells were also found in these livers, although such cells were rare as compared to human CD45+ or GUSB+ cells. In contrast, human cells were not detected in the livers of mice tansplanted with ALDHlolin− cells in any of our assays. Thus, ALDH-expressing progenitor cells demonstrated potent engraftment of variable cellular phenotypes, suggesting that these adult progenitor cells should be further explored in transplantation models of tissue damage. Our data also support the idea that hematopoietic stem cells may home to the injured liver and release trophic factors that hasten tissue repair, while direct differentiation of these stem cells to hepatocytes or fusion of these cells with hepatocytes is rare and contributes to a lesser extent to liver repair.
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Sumpter, Tina L., i Angus W. Thomson. "DAP12 renders liver dendritic cells resistant to maturation (91.14)". Journal of Immunology 182, nr 1_Supplement (1.04.2009): 91.14. http://dx.doi.org/10.4049/jimmunol.182.supp.91.14.
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Abstract Liver APC are constitutively exposed to gut-derived LPS, yet are refractory to LPS-induced maturation. We and others have hypothesized that resistance to LPS in liver DC reflects molecular inhibition of NF-κB activation. DNAX-activating protein of 12kDa (DAP12), a transmembrane adaptor protein, dampens co-stimulatory molecule and cytokine expression associated with inhibition of NF-κB in myeloid (m)DC. In this study, we evaluated the function of DAP12 in mDC (CD11c+CD11b+NK1.1-B220-) purified from livers or spleens of Fms-like tyrosine kinase 3 ligand (10 μg/day/10d)-mobilized C57BL/10 mice (in which DC populations were enriched), then cultured overnight with LPS. To test the hypothesis that DAP12 impairs LPS-induced maturation of liver mDC, DAP12 was silenced with siRNA (400nM) 2h prior to LPS stimulation. Liver mDC did not upregulate CD80, CD86, B7-H1 (PD-L1), B7RP or IL-12 to the extent of splenic mDC in response to LPS. Silencing DAP12 enhanced expression of CD80, CD86, IL-12 and the Th1-polarizing molecule, Delta4, but not B7-H1 or B7RP in liver and spleen mDC in response to LPS. These effects were more pronounced in liver mDC. We conclude that the comparatively immature state of liver mDC may be regulated, in part, by DAP12. Supported by American Liver Foundation and American Transplantation Society Fellowships and NIH RO1AI60994.
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Marangoni, Antonella, Rita Aldini, Vittorio Sambri, Marco Montagnani, Giorgio Ballardini, Elisa Storni i Roberto Cevenini. "Uptake and Killing of Leptospira interrogans and Borrelia burgdorferi, Spirochetes Pathogenic to Humans, by Reticuloendothelial Cells in Perfused Rat Liver". Infection and Immunity 68, nr 9 (1.09.2000): 5408–11. http://dx.doi.org/10.1128/iai.68.9.5408-5411.2000.
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ABSTRACT In situ-perfused rat livers were infused with a single dose of 1.5 × 107 radiolabeled cells of Leptospira interrogans serovar icterohaemorrhagiae, the agent of leptospirosis, or with Borrelia burgdorferi IRS, the agent of Lyme disease. Significant (P < 0.0001) differences in the liver uptake of L. interrogans and of B. burgdorferi were observed, the uptakes being 37.4% ± 2.3% for L. interrogans and 60.5% ± 3.1% for B. burgdorferi. Leptospires, in contrast to borreliae, were recovered from the livers when liver samples were cultured in growth medium. Leptospires but not borreliae were recovered in bile within 30 min of infusion. The association of leptospires and borreliae with reticuloendothelial cells of the liver was demonstrated by immunohistochemistry. Leptospires and borreliae were found to be associated with vimentin-positive cells and not with desmin-positive cells. Few leptospires but no borreliae were also seen associated with vimentin- and desmin-negative cells, suggesting the presence of leptospires outside the sinusoidal spaces, in the liver parenchyma.