Background/Aims The major histocompatibility class II (MHC II) transactivator, known as CIITA, is induced by Interferon gamma (IFN-γ) and plays a well-established role in regulating the expression of class II MHC molecules in antigen-presenting cells.
Methods Primary human hepatocytes (PHH) were isolated via therapeutic hepatectomy from two donors. The hepatocellular carcinoma (HCC) cell lines HepG2 and Huh7 were used for the mechanistic study, and HBV infection was performed in HepG2-NTCP cells. HBV DNA replication intermediates and secreted antigen levels were measured using Southern blotting and ELISA, respectively.
Results We identified a non-canonical function of CIITA in the inhibition of hepatitis B virus (HBV) replication in both HCC cells and patient-derived PHH. Notably, in vivo experiments demonstrated that HBV DNA and secreted antigen levels were significantly decreased in mice injected with the CIITA construct. Mechanistically, CIITA inhibited HBV transcription and replication by suppressing the activity of HBV-specific enhancers/promoters. Indeed, CIITA exerts antiviral activity in hepatocytes through ERK1/2-mediated down-regulation of the expression of hepatocyte nuclear factor 1α (HNF1α) and HNF4α, which are essential factors for virus replication. In addition, silencing of CIITA significantly abolished the IFN-γ-mediated anti-HBV activity, suggesting that CIITA mediates the anti-HBV activity of IFN-γ to some extent. HBV X protein (HBx) counteracts the antiviral activity of CIITA via direct binding and impairing its function.
Conclusions Our findings reveal a novel antiviral mechanism of CIITA that involves the modulation of the ERK pathway to restrict HBV transcription. Additionally, our results suggest the possibility of a new immune avoidance mechanism involving HBx.
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Most liver diseases lead to hepatic dysfunction with organ failure. Liver transplantation is the best curative
therapy, but it has some limitations such as donor shortage, possibility of rejection, and maintenance of
immunosuppressant. New therapies have been actively searched for over several decades, primarily in the form
of artificial liver support devices and hepatocyte transplantation, but both of these modalities remain
experimental. Stem cells have recently shown promise in cell therapy because they have the capacity for
self-renewal and multilineage differentiation, and are applicable to human diseases.
Very recent reports of unexpected plasticity in adult bone marrow have raised hopes of stem cell therapy
offering exciting therapeutic possibilities for patients with chronic liver disease. Both rodent and human
embryonic stem cells, bone marrow hematopoietic stem cells, mesenchymal stem cells, umbilical cord blood
cells, fetal liver progenitor cells, adult liver progenitor cells, and mature hepatocytes have been reported to be
capable of self-renewal, giving rise to daughter hepatocytes both in vivo and in vitro. These cells can
repopulate livers in animal models of liver injury and appear to be able to improve liver function. However,
significant challenges still exist before these cells can be used in humans, such as the lack of consensus about
the immunophenotype of liver progenitor cells, uncertainty of the physiological role of reported candidate
stem/progenitor cells, practicality of obtaining sufficient quantity of cells for clinical use, and concerns over
ethics, long-term efficacy, and safety. There have been reports of phase 1 trials using stem cell transplantation
in humans for liver diseases, but more effective trials are needed. We review the use of stem cells (focusing
on adult ones) and the reported human clinical trials, and highlight the challenges facing clinicians in their
quest to use liver stem cells to save lives. (Korean J Hepatol 2008;14:309-317)
Elimination of Reprogramming Transgenes Facilitates the Differentiation of Induced Pluripotent Stem Cells into Hepatocyte-like Cells and Hepatic Organoids Jaemin Jeong, Tae Hun Kim, Myounghoi Kim, Yun Kyung Jung, Kyeong Sik Kim, Sehwan Shim, Hyosun Jang, Won Il Jang, Seung Bum Lee, Dongho Choi Biology.2022; 11(4): 493. CrossRef
Hepatic patch by stacking patient-specific liver progenitor cell sheets formed on multiscale electrospun fibers promotes regenerative therapy for liver injury Yohan Kim, Young Won Kim, Seung Bum Lee, Kyojin Kang, Sangtae Yoon, Dongho Choi, Suk-Hee Park, Jaemin Jeong Biomaterials.2021; 274: 120899. CrossRef
In vitro differentiation effect of CCL4-induced liver injured mice serum on bone marrow-derived mesenchymal stem cells toward hepatocytes like cells Sulaiman Shams, Nazia Imran, Sahib Gul Afridi, Muhammad Ayaz, Atif Ali Khan Khalil, Abdul Nasir Cell and Tissue Banking.2021; 22(2): 297. CrossRef
Small-molecule-mediated reprogramming: a silver lining for regenerative medicine Yohan Kim, Jaemin Jeong, Dongho Choi Experimental & Molecular Medicine.2020; 52(2): 213. CrossRef
Exosomes derived from chemically induced human hepatic progenitors inhibit oxidative stress induced cell death Sujin Hyung, Jaemin Jeong, Kyusoon Shin, Ju Young Kim, Ji‐Hye Yim, Chan Jong Yu, Hyun Suk Jung, Kyung‐Gyun Hwang, Dongho Choi, Jong Wook Hong Biotechnology and Bioengineering.2020; 117(9): 2658. CrossRef
Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells Yohan Kim, Kyojin Kang, Seung Bum Lee, Daekwan Seo, Sangtae Yoon, Sung Joo Kim, Kiseok Jang, Yun Kyung Jung, Kyeong Geun Lee, Valentina M. Factor, Jaemin Jeong, Dongho Choi Journal of Hepatology.2019; 70(1): 97. CrossRef
Effect of human umbilical cord blood stem cell transplantation on oval cell response in 2-AAF/CCL4 liver injury model: experimental immunohistochemical study Hussein Abdellatif, Gamal Shiha, Dalia M. Saleh, Huda Eltahry, Kamal G. Botros Inflammation and Regeneration.2017;[Epub] CrossRef
Stem Cell Properties of Therapeutic Potential Geom Seog Seo The Korean Journal of Gastroenterology.2011; 58(3): 125. CrossRef
Pluripotent plasticity of stem cells and liver repopulation Luisa Gennero, Maria Augusta Roos, Kirk Sperber, Tetyana Denysenko, Paola Bernabei, Gian Franco Calisti, Mauro Papotti, Susanna Cappia, Roberto Pagni, Giuseppe Aimo, Giulio Mengozzi, Giovanni Cavallo, Stefano Reguzzi, Gian Piero Pescarmona, Antonio Ponzet Cell Biochemistry and Function.2010; 28(3): 178. CrossRef
Background Fulminant hepatic failure is a devastating process associated with high mortality, but no sequele after recovep. At the moment, there are no specific therapeutic modalities except for the orthotopic liver transplantation(OLT) which is limited to a small number of patients due to a lack of donor organ. Recently, several nonsurgical managements have been investigated to overcome the donor shortage and to bridge patients to OLT. These include artificial hepatic support systems, hepatocyte transplantation and extracorporeal liver support. Xenotransplantation is also being investigated to circumbent the donor shortage. Hepatocyte transplantation:The application of liver cell transplantation has been envisioned for temporary metabolic support during liver failure, provision of specific liver functions in inherited metabolic diseases of the liver and as a vehicle for ex vivo gene therapy. Potential advantages over OLT are that the procedure is simple, hepatoyctes can be cryopreserved for immediate use in need, the cost is less expensive and abrogation of allograft rejection may be easier by the modification of antigenicity during culture. Moreover, donor shortage can be overcome by the use of fetal hepatocytes, conditionally immortalized hepatocytes and possibly liver progenitor cells. However, the optimum route and the method are still being investigated. Recently, biodegradable matrix or cotransplantation with non-parencymal liver cells is used to improve and prolong the survival of transplanted hepatocytes in the peritoneum, and injection of donor type splenocytes into the thymus along with ablation of the peripheral lymphocytes with antilymphocyte globulin is adopted to tolerize the recipient to allogeneic hepatocytes. BioartiTicial liver:Presently, several bioartificial liver systems use mammalian hepatocytes held within cartridges, mostly hollow- fiber bioreactor perfused by plasma or whole blood. Plasma is separated from patient blood using Background:Fulminant hepatic failure is a devastating process associated with high mortality, but no sequele after recovep. At the moment, there are no specific therapeutic modalities except for the orthotopic liver transplantation(OLT) which is limited to a small number of patients due to a lack of donor organ. Recently, several nonsurgical managements have been investigated to overcome the donor shortage and to bridge patients to OLT. These include artificial hepatic support systems, hepatocyte transplantation and extracorporeal liver support. Xenotransplantation is also being investigated to circumbent the donor shortage. Hepatocyte transplantation:The application of liver cell transplantation has been envisioned for temporary metabolic support during liver failure, provision of specific liver functions in inherited metabolic diseases of the liver and as a vehicle for ex vivo gene therapy. Potential advantages over OLT are that the procedure is simple, hepatoyctes can be cryopreserved for immediate use in need, the cost is less expensive and abrogation of allograft rejection may be easier by the modification of antigenicity during culture. Moreover, donor shortage can be overcome by the use of fetal hepatocytes, conditionally immortalized hepatocytes and possibly liver progenitor cells. However, the optimum route and the method are still being investigated. Recently, biodegradable matrix or cotransplantation with non-parencymal liver cells is used to improve and prolong the survival of transplanted hepatocytes in the peritoneum, and injection of donor type splenocytes into the thymus along with ablation of the peripheral lymphocytes with antilymphocyte globulin is adopted to tolerize the recipient to allogeneic hepatocytes. BioartiTicial liver:Presently, several bioartificial liver systems use mammalian hepatocytes held within cartridges, mostly hollow- fiber bioreactor perfused by plasma or whole blood. Plasma is separated from patient blood using
Background/Aims Imrnortalized human fetal liver cell lines established by transfecting simian virus 40 T gene wae found to lose differentiated liver cell functions in successive long-term culture. Butyrate, known as a differentiation-promoting agent for a variety of cancer cell lines, is produced in the colon by bacterial flora and selectively transported into the liver though the portal blood flow. Therefe, butyrate might play a role in the maintenance of differentiation in hepatocytes in vivo. In thepresent study, the effects of butyrate on cell growth and differentiation in human fetal liver cell lines was investigated. Methods: Human fetal liver cell lines imrnortalized by SV 40 T antigen were treated with sodium butyrate (1mM), and cell growth rate after butyrate treatment were nmsured by the number of viable cells, determined by trypan blue dye exclusice method. The effects of sodium butyrate on the hepatocyte-specific differentiatian were assessed by albumin and alfa-fetoprotein (AFP) mRNA expression, analyzed using reverse-transcription polymerase chain reaction, and were also by the increment of albumin secretion into culture media, determined by a competitive inhibition ELISA. Results: Treatment with sodium butyrate resulted in a cessation of cellular proliferation and alterations in cellular morphology (increased cell size and polygonal change in shape). The level of albumin mRNA after sodium butyrate treatment was elevated by about two times as compared to that of control. In contrast, AFP mRNA expression were dennstrated neither before nor after sodium butyrate treatment. The average amount of albumin released in the medium was less than 6pghnl/10'cells/2days in the absence of sodium butyrate, and increased to 17 p g/ml/10'cells/2days at day 2, 21ugfml 10'cells/2days at day 4 in the presence of sodium butyrate, and these levels thereafter were over 10 times higher than that in the absence of sodium butyrate until day 10. Conclusion: These mults indicate that treatment of immcetalized fetal liver cell lines with butyrate leads to inhibition of cellular proliferation and promotion of adult hepatocyte-specific differentiation. (Korean J Hepatol 1997;6:193 201)
Background/Aims : Various techniques of hepatocyte transplantation were actively studied as an alternative to liver transplantation, because of the difficulty of obtaining donor organ, technical difficulties, and high cost. Isolated hepatocytes could be appropriately banked and distributed on demand. We tried to investigate the effect of intrasplenic transplantation of allogenic cryopreserved hepatocytes, into spleen prior to 90% partial hepatectomy in rats, on the survival rate. Methods : Cryopreserved hepatocytes, isolated by collagenase perfusion of the liver via the portal vein, were thawed and transplanted into the spleen of rats prior to induction of acute hepatic failure by resection of all lobes except caudate lobe (2.0×107 hepatocytes/rat). Results : 1. The viability of freshly isolated hepatocyte was 70-85%, but cell viability after cryopreservation 30-50%. 2. Difference of survival in control and transplant group is not statistically significant. but the survival rate, 48 hours after 90% partial hepatectomy, for control (7) and transplanted group (11) were 0% and 18%, respectively. 3. Although the glucose reduction gradient was not significantly different between two groups, it was more prominent in the control group than in the transplanted group. 4. Engraftment and survival of transplanted hepatocytes were noted in the spleen 2 days after transplantation. Conclusions : We could not observe statistically significant improvement of survival with intrasplenic transplantation of cryopreserved hepatocytes in rats with 90% partial hepatectomy-induced acute liver failure. However, 18% survival after 90% partial hepatectomy was noted in the transplanted group, compared to no survival in the control group. This suggests that intrasplenic transplantation of cryopreserved hepatocytes might be effective in the treatment of acute liver failure. (Korean J Hepatol 1999;5:116－123)
Background/Aims This study was aimed to examine if FB1 induced-hepatotoxicity involves apoptosis, and cholesteryl hemisuccinate (CS) pre-treatment would selectively interfere with FB1 induced-apoptosis of hepatocytes. Methods: Sprague-Dawley rats were intravenousely injected with FB1 (1.25 mg/kg/day) for two days, and were sacrificed at 3, 6, 12, 24 and 48 hours after injection. Another experiment group was composed of rats with pretreatment of CS (100 mg/kg/day, i.p.) before FB1 injection. Results: This study demonstrated that administration of hepatotoxic dose of FB1 to Sprague-Dawley rats resulted in liver injury leading to cell death by apoptosis. FB1-induced apoptosis was preceded by early elevation in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, and appearance of injured pre-apoptotic cells at 12 hours was followed by massive fragmentation and margination of heterochromatin at 24 hours. CS pre-treatment prior to FB1 injection ameliorated serum biochemistry and hepatic injury with apoptosis, demonstrated by histological, ultrastructural and TUNEL (terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling) methods. In addition, there was remarkable decrease in number of PCNA (proliferative cell nuclear antigen)-positive proliferating hepatocytes compared to that of FB1 treated group. Conclusion: This study suggests that apoptosis significantly contributes to FB1-induced hepatotoxicity in vivo, and pre-exposure of rat to CS prevents FB1-induced hepatic apoptosis and proliferation. (Korean J Hepatol 1999;5:227－239)
Background/Aims During cryopreservation of hepatocytes, a dramatic loss in cell number, viability and differentiated cell function is usually inevitable because hepatocytes are very sensitive to stress during freezing and thawing. We tried to investigate the optimal cryopreservation conditions of hepatocytes including the constituents of the freezing medium and freezing rate.Methods:Isolated hepatocytes were cryopreserved in media containing 10% glycerol or dimethyl sulfoxide(DMSO) of variable concentration. Different freezing procedures(stepwise, rapid, and programmed with or without shock cooling) were used and they were stored in a liquid nitrogen tank. After rapid thawing at 39℃, followed by dilution and removal of the cryopreservative, the ability of the hepatocytes to exclude trypan blue dye(TB) was evaluated. Hepatocytes were fractionated through a Nycodenz density gradient centrifugation(DGC) to eliminate dead cells. Cells were plated on dishes coated with type I collagen.Results:Cell viability of hepatocytes recovered from cryopreservation was maintained better using 10, 15, and 20% DMSO as a cryopreservative and programmed cell freezer with shock cooling. After Nycodenz DGC a hepatocyte fraction highly enriched in viable cells could be taken between 11% and 30%. In culture, cryopreserved hepatocytes exhibited a morphology with epithelial characteristics.Conclusions:These results suggest that rate-adjusted programmed freezing with shock cooling and 10, 15 and 20% DMSO increased the viability of cryopreserved hepatocytes. The hepatocyte fraction highly enriched in viable cells could be taken using Nycodenz DGC. In order to establish a bank of hepatocytes for hepatocyte transplantations and artificial livers a more improved method is nevertheless necessary to increase the viability of hepatocytes after cryopreservation.(Korean J Hepatol 2001;7:308-314)
Background/Aims Acute hepatic failure is a serious problem. Its mortality reaches up to 80%. Only liver transplantation has been accepted as a definite treatment for patients with hepatic failure but shortage of donor organs is the main obstacle of this approach. A possible solution to this problem is a bioartificial liver system, perfusion of patients blood to isolated hepatocyte. In this study, we performed the isolation and culture of pig hepatocyte in large scale for the application of bioartificial liver system. Methods: Hepatocyte isolation was performed by two-step collagenase method via portal vein perfusion in 10kg female pigs. After that, we compared the functional differences of the spheroid culture to the monolayer culture of hepatocyte. The viability and the function of hepatocyte were assessed using trypan-blue exclusion test and the measurement of the rate of ureagenesis and ammonia removal. Results: The average viability and yield of hepatocyte were 86.8±8.0 % and 7.8±5.4×109, respectively. The spheroid culture was superior to the monolayer culture in functional aspect of hepatocyte, and their differences, especially for ammonia removal, were more apparent in parallel with culture time. Conclusions: For hepatocyte isolation, we obtained sufficient viability and yield of hepatocyte for clinical usage of bioartificial liver system. The function of hepatocyte seems to be better in the spheroid culture than in the monolayer culture. Further studies are needed for application of bioartificial liver system in clinical setting. (Korean J Hepatol 2002;8:249-255)
Despite the small size of its genome (3.2 kb) and having only four genes that are encoded within it, the hepatitis B virus (HBV) is one of the most successful viral pathogens in human history. It is estimated that there are about 350-400 million people wo
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