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Lee J.-H.,Samsung | Lee D.-H.,Lifeliver. Co. | Park J.-K.,Dongguk University | Kim S.-K.,Pukyong National University | And 2 more authors.
Transplantation Proceedings | Year: 2012

The development of bioartificial liver (BAL) systems has required detailed information about the functional capabilities of cultured hepatocytes during blood or plasma passage. In this study we investigated the effects of porcine plasma and various supplements on the viability and function of adult rat hepatocytes in vitro. Primary rat hepatocytes cultured in porcine plasma supplemented with various substances showed albumin synthesis rates and viability equal to or higher than those of controls. Supplementation with calcium chloride, magnesium sulfate, trace elements, amino acids, insulin, and epidermal growth factor were essential to maintain viability and high albumin synthesis. Especially, trace elements showed significantly higher and longer albumin secretion. Isolated rat hepatocytes were cultured in Spinner flasks for 24 hours to form spheroids that were harvested and encapsulated with chitosan-alginate solution before transfer to the bioreactor in the BAL system. Encapsulated rat hepatocyte spheroids cultured with porcine plasma including trace elements showed higher viability (57%) than controls (40%) after 24 hours, with ammonia removal values of 30.92 μg/10 6 cells versus the control 9.04 μg/10 6 cells. After 24 hours of operation the urea secretion value of encapsulated rat hepatocyte spheroids cultured in porcine plasma in the presence versus absence of trace elements was 76.73 μg/10 6 cells and 18.80 μg/10 6 cells, respectively. We concluded that encapsulated hepatocyte spheroids in a packed-bed bioreactor operated with human plasma including trace elements enhanced cell viability and liver function as a bases for an in vivo clinical trial of the BAL system. © 2012 Elsevier Inc.


Lee J.-H.,Samsung | Park H.-J.,Samsung | Kim Y.-A.,Samsung | Lee D.-H.,Lifeliver Co Ltd | And 4 more authors.
Transplantation Proceedings | Year: 2012

Liver transplantation is the only effective treatment for end-stage liver disease. Because of the limited donor availability, attention has been focused on the possibility to restore liver mass and function through cell transplantation. Stem cells are a promising source for liver repopulation after cell transplantation, but whether or not the adult liver contains hepatic stem cells is highly controversial. Several studies have suggested the presence of stem cells in the adult normal human liver. However, a population with stem cell properties has not yet been isolated. The purpose of this study was to identify and characterize progenitor cells in normal adult human liver. We isolated and expanded human liver stem cells (HLSCs) from a donated liver not suitable for liver transplantation or characterizing them by fluorescence-activated cell sorter, polymerase chain reaction, and immunofluorescence assay. HLSCs expressed the mesenchymal stem cell markers CD29, CD73, CD44, CD90, CD105, and CD166 but not the hematopoietic stem cell markers CD34, CD45, and CD117. HLSCs were also positive for vimentin and nestin, a stem cell marker. The absence of staining for cytokeratin-19, CD117, and CD34 indicated that HLSCs were not oval stem cells. In addition, HLSCs expressed CD26, and in a small percentage of cells, cytokeratin-8 and cytokeratin-18, indicating a partial commitment to hepatic cells. We concluded that HLSCs expressed several mesenchymal but not hematopoietic stem cell markers as well as CD26 and CK18, indicating a partial commitment to hepatic cells. © 2012 Elsevier Inc.


Eom Y.W.,Yonsei University | Eom Y.W.,Lifeliver Co. | Lee J.E.,Lifeliver Co. | Yang M.S.,Lifeliver Co. | And 9 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

Stem cell therapy for muscular dystrophies requires stem cells that are able to participate in the formation of new muscle fibers. However, the differentiation steps that are the most critical for this process are not clear. We investigated the myogenic phases of human adipose tissue-derived stem cells (hASCs) step by step and the capability of myotube formation according to the differentiation phase by cellular fusion with mouse myoblast C2C12 cells. In hASCs treated with 5-azacytidine and fibroblast growth factor-2 (FGF-2) for 1. day, the early differentiation step to express MyoD and myogenin was induced by FGF-2 treatment for 6. days. Dystrophin and myosin heavy chain (MyHC) expression was induced by hASC conditioned medium in the late differentiation step. Myotubes were observed only in hASCs undergoing the late differentiation step by cellular fusion with C2C12 cells. In contrast, hASCs that were normal or in the early stage were not involved in myotube formation. Our results indicate that stem cells expressing dystrophin and MyHC are more suitable for myotube formation by co-culture with myoblasts than normal or early differentiated stem cells expressing MyoD and myogenin. © 2011 Elsevier Inc.


Lee J.-H.,Samsung | Park H.-J.,Samsung | Jang I.K.,Lifeliver Co Ltd | Kim H.-E.,Lifeliver Co Ltd | And 4 more authors.
Transplantation Proceedings | Year: 2014

Liver transplantation is severely limited by donor shortage although it is the only effective treatment for end-stage liver disease. So the best alternative is hepatocyte transplantation. For obtaining human hepatocytes, some stem cells originating from extrahepatic or intraheptic tissues have been isolated and characterized. Previously we have reported that human liver-derived stem cells (HLSCs) could be isolated and expanded from donated livers unsuitable for transplantation; they expressed some markers of mesenchymal stem cells but neither hematopoietic nor oval cells. In this study, we isolated and expanded HLSCs with mesenchymal characteristics from another adult human liver. They showed mesenchymal morphology and grew well under serum condition similar to our previous reports. Also, they expressed some markers of mesenchymal stem cells, such as CD44, CD73, CD90, and CD105, through fluorescence-activated cell sorting analysis. When HLSCs were sequentially exposed to fibroblast growth factor-1 (FGF-1), FGF-4, and hepatocyte growth factor (HGF) followed by FGF-4, HGF, oncostatin M, and dexamethasone, they became round or polygonal, and expressed some hepatic markers such as albumin and α1-antitrypsin in the gene or protein level. Also, they showed urea synthesis activity 7 days after treatment of FGF-4, HGF, oncostatin M, and dexamethasone. These results provided that HLSCs would be a useful cell source in the field of regenerative medicine as well as liver cell biology. © 2014 by Elsevier Inc. All rights reserved.


Jang I.K.,Ajou University | Jang I.K.,Lifeliver Co Ltd | Yoon H.H.,Dongguk University | Yang M.S.,Lifeliver Co Ltd | And 5 more authors.
Transplantation Proceedings | Year: 2014

B7-H1 on mesenchymal stem cells (MSCs) is known to modulate immune response. However, its expression pattern and exact immunomodulatory mechanism are unclear. In this study, we examined the immunomodulatory mechanism through the expression pattern of B7-H1 and major histocompatibility complex class II in various MSCs. Human bone marrow, adipose tissue, and cord blood MSCs were isolated and cultured. B7-H1, HLA-ABC, and HLA-DR expression on MSCs by interferon-γ (IFN-γ) was detected time-dependently by flow cytometry. The inhibitory effect of MSCs on T lymphocytes was observed in phytohemagglutinin antigen-induced T cell proliferation assay. The expression of B7-H1 was rapidly induced, but the expression of HLA-DR was induced at 48 hours after IFN-γ treatment. The inhibitory effect of MSCs on T cell proliferation could be restored when the anti-B7-H1 monoclonal antibody was used to block the B7-H1, or when the HLA-DRα small interfering RNA was used to interfere with its expression. These results show that MSCs could inhibit the T cell proliferation and activation by B7-H1 depending on the presence of HLA-DR. Therefore, MSCs would have a strong effect on immune diseases such as graft-versus-host disease and autoimmune diseases when MSCs are primed with IFN-γ 48 hours before transplantation. © 2014 by Elsevier Inc. All rights reserved.


Lee J.-H.,Samsung | Park H.-J.,Samsung | Kim Y.-A.,Samsung | Lee D.-H.,Lifeliver Co | And 4 more authors.
Transplantation Proceedings | Year: 2012

Stem cells are a promising source for liver repopulation after cell transplantation, but whether the adult liver contains hepatic stem cells is controversial. The purpose of this study was to characterize the properties and expression profile of major histocompatibility complex (MHC) antigens on the surface of human-derived stem cells. Human liver-derived stem cells (HLSC7) were isolated from the nontumorous tissue of a patient who underwent a resection of an hepatic hemangioendothelioma. We characterized HLSC7 using a fluorescence-activated cell sorter, polymerase chain reactions, and immunofluorescence assays. HLSC7 expressed mesenchymal but not hematopoietic stem cell markers. HLSC7 underwent osteogenic, chondrogenic, and hepatogenic differentiation when cultured in appropriate differentiation media. However, HLSC7 did not differentiate into adipocytes. In addition, HLSC7 did not express MHC class II (HLA-DP, -DQ, and -DR) antigens. However, they did express MHC class I antigens. These results suggest that human liver-derived stem cells express MHC class I antigens and thus may be rejected on transplantation. Therefore, in addition to studies on stem cell differentiation, one must overcome immunologic barriers for successful clinical application of this therapy. © 2012 Elsevier Inc.


PubMed | Lifeliver Co Ltd, Sungkyunkwan University, Dongguk University and Samsung
Type: Journal Article | Journal: Transplantation proceedings | Year: 2014

Liver transplantation is severely limited by donor shortage although it is the only effective treatment for end-stage liver disease. So the best alternative is hepatocyte transplantation. For obtaining human hepatocytes, some stem cells originating from extrahepatic or intraheptic tissues have been isolated and characterized. Previously we have reported that human liver-derived stem cells (HLSCs) could be isolated and expanded from donated livers unsuitable for transplantation; they expressed some markers of mesenchymal stem cells but neither hematopoietic nor oval cells. In this study, we isolated and expanded HLSCs with mesenchymal characteristics from another adult human liver. They showed mesenchymal morphology and grew well under serum condition similar to our previous reports. Also, they expressed some markers of mesenchymal stem cells, such as CD44, CD73, CD90, and CD105, through fluorescence-activated cell sorting analysis. When HLSCs were sequentially exposed to fibroblast growth factor-1 (FGF-1), FGF-4, and hepatocyte growth factor (HGF) followed by FGF-4, HGF, oncostatin M, and dexamethasone, they became round or polygonal, and expressed some hepatic markers such as albumin and 1-antitrypsin in the gene or protein level. Also, they showed urea synthesis activity 7 days after treatment of FGF-4, HGF, oncostatin M, and dexamethasone. These results provided that HLSCs would be a useful cell source in the field of regenerative medicine as well as liver cell biology.


PubMed | Ajou University, Lifeliver Co Ltd, Sungkyunkwan University and Dongguk University
Type: Journal Article | Journal: Transplantation proceedings | Year: 2014

B7-H1 on mesenchymal stem cells (MSCs) is known to modulate immune response. However, its expression pattern and exact immunomodulatory mechanism are unclear. In this study, we examined the immunomodulatory mechanism through the expression pattern of B7-H1 and major histocompatibility complex class II in various MSCs. Human bone marrow, adipose tissue, and cord blood MSCs were isolated and cultured. B7-H1, HLA-ABC, and HLA-DR expression on MSCs by interferon- (IFN-) was detected time-dependently by flow cytometry. The inhibitory effect of MSCs on T lymphocytes was observed in phytohemagglutinin antigen-induced T cell proliferation assay. The expression of B7-H1 was rapidly induced, but the expression of HLA-DR was induced at 48 hours after IFN- treatment. The inhibitory effect of MSCs on T cell proliferation could be restored when the anti-B7-H1 monoclonal antibody was used to block the B7-H1, or when the HLA-DR small interfering RNA was used to interfere with its expression. These results show that MSCs could inhibit the T cell proliferation and activation by B7-H1 depending on the presence of HLA-DR. Therefore, MSCs would have a strong effect on immune diseases such as graft-versus-host disease and autoimmune diseases when MSCs are primed with IFN- 48 hours before transplantation.


PubMed | Yonsei University, Lifeliver Inc and Hanyang University
Type: Journal Article | Journal: Cell medicine | Year: 2016

Although intravenous administration of mesenchymal stem cells (MSCs) can enhance functional recovery after spinal cord injury (SCI), the underlying mechanisms have to be elucidated. In this study, we explored the mechanisms for functional recovery in SCI rats after intravenous transplantation of MSCs derived from human umbilical cord blood. Sprague-Dawley rats were randomly assigned to receive either MSCs (110(6) cells/0.5 ml) or PBS into the tail vein immediately after SCI. They were then evaluated by the Basso-Beattie-Bresnahan (BBB) locomotor rating scale weekly for 8 weeks and by somatosensory evoked potentials (SSEPs) 8 weeks after transplantation. MSC-treated rats showed a modest but significant improvement in BBB scores and latencies of SSEPs, compared with PBS controls. When human-specific Alu element was measured in the spinal cord, it was detected only 1 h after transplantation, suggesting transient engraftment of MSCs. Inflammatory cytokines were also determined using RT-PCR or Western blot in spinal cord extracts. In MSC-treated rats, the level of proinflammatory cytokine IL-1 was decreased, but that of anti-inflammatory cytokine IL-10 was increased. MSCs also immediately suppressed IL-6 at 1 h posttransplantation. However, the response of IL-6, which has an immunoregulatory role, was increased 1-3 days after transplantation. In addition, we quantified microglia/macrophage stained with Iba-1 around the damaged spinal cord using immunohistochemistry. A proportion of activated microglia and macrophages in total Iba-1(+) cells was significantly decreased in MSC-treated rats, compared with PBS controls. These results suggest that early immunomodulation by intravenously transplanted MSCs is a potential underlying mechanism for functional recovery after SCI.


PubMed | Sungkyunkwan University, Samsung, Dongguk University and Lifeliver Co.
Type: Journal Article | Journal: Transplantation proceedings | Year: 2015

Many types of stem cells have been widely used for the treatment of liver diseases. The therapeutic effect of stem cells is predominantly based on the immune regulatory properties of these cells.We isolated human liver stem cells (HLSCs), which are considered intrahepatic stem cells, and examined their suppression of T-cell proliferation induced by phytohemagglutinin.HLSCs inhibited phytohemagglutinin-induced T-cell proliferation not only in direct co-culture but also in indirect co-culture in a cell number-dependent manner. That is, T-cell proliferation was substantially inhibited by cell-to-cell contact regardless of soluble factor(s). B7-H1, a co-inhibitory molecule that relies on cell-to-cell contact, was found to be constitutively expressed at low levels on HLSCs. Furthermore, its expression was upregulated moderately by tumor necrosis factor- and dramatically by interferon-.These results suggest that HLSCs would have therapeutic effects through T-cell suppression in acute liver diseases.

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