The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Hidekazu Tsukamoto - One of the best experts on this subject based on the ideXlab platform.

  • septum transversum derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse Liver
    Hepatology, 2011
    Co-Authors: Kinji Asahina, William T Pu, Bin Zhou, Hidekazu Tsukamoto
    Abstract:

    The septum transversum mesenchyme (STM) signals to induce hepatogenesis from the foregut endoderm. Hepatic stellate cells (HSCs) are sinusoidal pericytes assumed to originate from the STM and participate in mesenchymal-epithelial interaction in embryonic and adult Livers. However, the Developmental origin of HSCs remains elusive due to the lack of markers for STM and HSCs. We previously identified submesothelial cells (SubMCs) beneath mesothelial cells (MCs) as a potential precursor for HSCs in developing Livers. In the present study, we reveal that both STM in embryonic day (E) 9.5 and MC/SubMCs in E12.5 share the expression of activated leukocyte cell adhesion molecule (Alcam), desmin, and Wilms tumor 1 homolog (Wt1). A cell lineage analysis using MesP1Cre/Rosa26lacZflox mice identifies the mesodermal origin of the STM, HSCs, and perivascular mesenchymal cells (PMCs). A conditional cell lineage analysis using the Wt1CreERT2 mice demonstrates that Wt1+ STM gives rise to MCs, SubMCs, HSCs, and PMCs during Liver Development. Furthermore, we find that Wt1+ MC/SubMCs migrate inward from the Liver surface to generate HSCs and PMCs including portal fibroblasts, smooth muscle cells, and fibroblasts around the central veins. On the other hand, the Wt1+ STM and MC/SubMCs do not contribute to sinusoidal endothelial cells, Kupffer cells, and hepatoblasts. Conclusion: our results demonstrate that HSCs and PMCs are derived from MC/SubMCs, which are traced back to mesodermal STM during Liver Development. (HEPATOLOGY 2011;.)

  • mesenchymal origin of hepatic stellate cells submesothelial cells and perivascular mesenchymal cells during mouse Liver Development
    Hepatology, 2009
    Co-Authors: Kinji Asahina, Hidekazu Tsukamoto, Shirley Y Tsai, Mamoru Ishii, Robert E Maxson, Henry M Sucov
    Abstract:

    The knowledge concerning fetal hepatic stellate cells (HSCs) is scarce, and their cell lineage and functions are largely unknown. The current study isolated fetal Liver mesenchymal cells from a mouse expressing β-galactosidase under the control of Msx2 promoter by fluorescence-activated cell sorting (FACS) and surveyed marker genes by microarray analysis. Based on the location and immunostaining with conventional and newly disclosed markers, we have identified three distinct populations of fetal Liver mesenchymal cells expressing both desmin and p75 neurotrophin receptor (p75NTR): HSCs in the Liver parenchyma; perivascular mesenchymal cells expressing α-smooth muscle actin (α-SMA); and submesothelial cells associated with the basal lamina beneath mesothelial cells and expressing activated leukocyte cell adhesion molecule (ALCAM) and platelet-derived growth factor receptor α. A transitional cell type from the submesothelial cell phenotype to fetal HSCs was also identified near the Liver surface. Mesothelial cells expressed podoplanin and ALCAM. Ki-67 staining showed that proliferative activity of the submesothelial cells is higher than that of mesothelial cells and transitional cells. Using anti-ALCAM antibodies, submesothelial and mesothelial cells were isolated by FACS. The ALCAM+ cells expressed hepatocyte growth factor and pleiotrophin. In culture, the ALCAM+ cells rapidly acquired myofibroblastic morphology and α-SMA expression. The ALCAM+ cells formed intracellular lipid droplets when embedded in collagen gel and treated with retinol, suggesting the potential for ALCAM+ cells to differentiate to HSCs. Finally, we demonstrated that fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are all derived from mesoderm by using MesP1-Cre and ROSA26 reporter mice. Conclusion: Fetal HSCs, submesothelial cells, and perivascular mesenchymal cells are mesodermal in origin, and ALCAM+ submesothelial cells may be a precursor for HSCs in developing Liver. (HEPATOLOGY 2009.)

Christopher A Bradfield - One of the best experts on this subject based on the ideXlab platform.

  • abnormal Liver Development and resistance to 2 3 7 8 tetrachlorodibenzo p dioxin toxicity in mice carrying a mutation in the dna binding domain of the aryl hydrocarbon receptor
    Toxicological Sciences, 2008
    Co-Authors: Maureen K Bunger, Susan M Moran, E W N Glover, Garet P Lahvis, Jacqueline A Walisser, Erin L Hsu, Christopher A Bradfield
    Abstract:

    The aryl hydrocarbon receptor (AHR) is known for its role in the adaptive and toxic responses to a large number of environmental contaminants, as well as its role in hepatovascular Development. The classical AHR pathway involves ligand binding, nuclear translocation, heterodimerization with the AHR nuclear translocator (ARNT), and binding of the heterodimer to dioxin response elements (DREs), thereby modulating the transcription of an array of genes. The AHR has also been implicated in signaling events independent of nuclear localization and DNA binding, and it has been suggested that such pathways may play important roles in the toxicity of 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). Here, we report the generation of a mouse model that expresses an AHR protein capable of ligand binding, interactions with chaperone proteins, functional heterodimerization with ARNT, and nuclear translocation, but is unable to bind DREs. Using this model, we provide evidence that DNA binding is required AHR-mediated Liver Development, as Ahr dbd/dbd mice exhibit a patent ductus venosus, similar to what is seen in Ahr 2/2 mice. Furthermore, Ahr dbd/dbd mice are resistant to TCDD

  • resistance to 2 3 7 8 tetrachlorodibenzo p dioxin toxicity and abnormal Liver Development in mice carrying a mutation in the nuclear localization sequence of the aryl hydrocarbon receptor
    Journal of Biological Chemistry, 2003
    Co-Authors: Maureen K Bunger, Susan M Moran, E W N Glover, Tami L Thomae, Garet P Lahvis, Bernice C Lin, Christopher A Bradfield
    Abstract:

    Abstract The Ah receptor (AHR) mediates the metabolic adaptation to a number of planar aromatic chemicals. Essential steps in this adaptive mechanism include AHR binding of ligand in the cytosol, translocation of the receptor to the nucleus, dimerization with the Ah receptor nuclear translocator, and binding of this heterodimeric transcription factor to dioxin-responsive elements (DREs) upstream of promoters that regulate the expression of genes involved in xenobiotic metabolism. The AHR is also involved in other aspects of mammalian biology, such as the toxicity of molecules like 2,3,7,8-tetrachlorodibenzo-p-dioxin as well as regulation of normal Liver Development. In an effort to test whether these additional AHR-mediated processes require a nuclear event, such as DRE binding, we used homologous recombination to generate mice with a mutation in the AHR nuclear localization/DRE binding domain. These Ahr nls mice were found to be resistant to all 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxic responses that we examined, including hepatomegaly, thymic involution, and cleft palate formation. Moreover, aberrations in Liver Development observed in these mice were identical to that observed in mice harboring a null allele at the Ahr locus. Taken in sum, these data support a model where most, if not all, of AHR-regulated biology requires nuclear localization.

Stefano Cairo - One of the best experts on this subject based on the ideXlab platform.

  • wnt signaling and hepatocarcinogenesis the hepatoblastoma model
    The International Journal of Biochemistry & Cell Biology, 2011
    Co-Authors: Carolina Armengol, Stefano Cairo, Monique Fabre, Marieannick Buendia
    Abstract:

    The Wnt/β-catenin pathway plays a key role in Liver Development, regeneration and tumorigenesis. Among human cancers tightly linked to abnormal Wnt/β-catenin signaling, hepatoblastoma (HB) presents with the highest rate (50-90%) of β-catenin mutations. HB is the most common malignant tumor of the Liver in childhood. This embryonic tumor differs from hepatocellular carcinoma by the absence of viral etiology and underlying Liver disease, and by distinctive morphological patterns evoking hepatoblasts, the bipotent precursors of hepatocytes and cholangiocytes. Recent studies of the molecular pathogenesis of hepatoblastoma have led to identify two major tumor subclasses resembling early and late phases of prenatal Liver Development and presenting distinctive chromosomal alterations. It has been shown that the molecular signature of Wnt/β-catenin signaling in hepatoblastoma is mainly imposed by Liver context, but differs according to Developmental stage. Finally, the differentiation stage of tumor cells strongly influences their invasive and metastatic properties, therefore affecting clinical behavior.

  • hepatic stem like phenotype and interplay of wnt β catenin and myc signaling in aggressive childhood Liver cancer
    Cancer Cell, 2008
    Co-Authors: Stefano Cairo, Carolina Armengol, Aurelien De Reynies, Yu Wei, Emilie Thomas, Claireangelique Renard
    Abstract:

    Hepatoblastoma, the most common pediatric Liver cancer, is tightly linked to excessive Wnt/beta-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of Liver Development and a discriminating 16-gene signature. beta-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.

  • hepatic stem like phenotype and interplay of wnt β catenin and myc signaling in aggressive childhood Liver cancer
    Cancer Cell, 2008
    Co-Authors: Stefano Cairo, Carolina Armengol, Aurelien De Reynies, Emilie Thomas, Claireangelique Renard, Andrei Goga, Asha Balakrishnan
    Abstract:

    Summary Hepatoblastoma, the most common pediatric Liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of Liver Development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy.

Atsushi Miyajima - One of the best experts on this subject based on the ideXlab platform.

  • stem progenitor cells in Liver Development homeostasis regeneration and reprogramming
    Cell Stem Cell, 2014
    Co-Authors: Atsushi Miyajima, Minoru Tanaka, Tohru Itoh
    Abstract:

    The Liver is a central organ for homeostasis with unique regenerative capacities. Mature hepatocytes possess a remarkable capacity to proliferate upon injury, challenging efforts to discern the role of adult Liver stem cells in this process. In contrast, stem/progenitor cells in the developing Liver have been extensively characterized, and these investigations have informed efforts to produce functional hepatocytes in vitro for cell therapy and drug screening. In this Review, we describe recent advances in the characterization of Liver stem cells and discuss evidence supporting and refuting whether self-renewable and bipotential Liver stem cells exist in Development, homeostasis, regeneration, and disease.

  • mouse hepatoblasts at distinct Developmental stages are characterized by expression of epcam and dlk1 drastic change of epcam expression during Liver Development
    Mechanisms of Development, 2009
    Co-Authors: Minoru Tanaka, Mayuko Okabe, Yoshiko Kamiya, Yuko Tsukahara, Kaori Suzuki, Shigeru Saito, Atsushi Miyajima
    Abstract:

    Abstract Hepatoblasts are hepatic progenitor cells that expand and give rise to either hepatocyte or cholangiocytes during Liver Development. We previously reported that delta-like 1 homolog (DLK1) is expressed in the mouse Liver primordium at embryonic day (E) 10.5 and that DLK1+ cells in E14.5 Liver contain high proliferative and bipotential hepatoblasts. While the expression of epithelial cell adhesion molecule (EpCAM) in hepatic stem/progenitor cells has been reported, its expression profile at an early stage of Liver Development remains unknown. In this study, we show that EpCAM is expressed in mouse Liver bud at E9.5 and that EpCAM+DLK1+ hepatoblasts form hepatic cords at the early stage of hepatogenesis. DLK1+ cells of E11.5 Liver were fractionated into EpCAM+ and EpCAM− cells; one forth of EpCAM+DLK1+ cells formed a colony in vitro whereas EpCAM−DLK1+ cells rarely did it. Moreover, EpCAM+DLK1+ cells contained cells capable of forming a large colony, indicating that EpCAM+DLK1+ cells in E11.5 Liver contain early hepatoblasts with high proliferation potential. Interestingly, EpCAM expression in hepatoblasts was dramatically reduced along with Liver Development and the colony-forming capacities of both EpCAM+DLK1+ and EpCAM−DLK1+ cells were comparable in E14.5 Liver. It strongly suggested that most of mouse hepatoblasts are losing EpCAM expression at this stage. Moreover, we provide evidence that EpCAM+DLK1+ cells in E11.5 Liver contain extrahepatic bile duct cells as well as hepatoblasts, while EpCAM−DLK1+ cells contain mesothelial cell precursors. Thus, the expression of EpCAM and DLK1 suggests the Developmental pathways of mouse Liver progenitors.

  • hepatoma derived growth factor is highly expressed in developing Liver and promotes fetal hepatocyte proliferation
    Hepatology, 2002
    Co-Authors: Hirayuki Enomoto, Atsushi Miyajima, Taisei Kinoshita, Kenya Yoshida, Yoshihiko Kishima, Mitsunari Yamamoto, Allen D Everett, Hideji Nakamura
    Abstract:

    Hepatoma-derived growth factor (HDGF) is a heparin-binding protein, which has been purified from the conditioned media of HuH-7 hepatoma cells. Recent studies have suggested the involvement of HDGF in Development of the kidney and cardiovascular systems. In the present study, we investigated the possibility that HDGF was also involved in Liver Development. Northern blot and immunostaining revealed unique expression patterns of HDGF in Liver Development. HDGF expression was strongly detected in the fetal Liver of the midgestation stage and was markedly decreased near birth. Its expression was mainly detected in stromal cells, including immature hepatocytes. Expression in hepatocytes decreased with differentiation. Administration of recombinant HDGF enhanced the growth of primary cultured fetal hepatocytes significantly, although the effect was small. The effect of exogenous HDGF on the proliferation of neonatal hepatocytes was also small and significant only at one point, despite the lower expression of endogenous HDGF, suggesting that the differences exist between fetal and neonatal hepatocytes. However, adenoviral introduction of HDGF antisense cDNA into the fetal hepatocytes significantly suppressed their proliferation, and the inhibitory effect of HDGF antisense virus was reversed by exogenous HDGF. In conclusion, HDGF helps regulate the hepatocyte proliferation in Liver Development.

  • STAT3 Down-regulates the Expression of Cyclin D during Liver Development
    Journal of Biological Chemistry, 2002
    Co-Authors: Takaaki Matsui, Taisei Kinoshita, Toshio Hirano, Takashi Yokota, Atsushi Miyajima
    Abstract:

    Abstract As the expression of cyclin D1 is induced during Liver regeneration and also in hepatic tumor cells, cyclin D1 is likely to play an important role in the proliferation and transformation of hepatocytes. However, the role of cyclin D1 in Liver Development remains unknown. Here we show that the expression of D-type cyclins including cyclin D1, D2, and D3 is down-regulated along with Liver Development. In addition, oncostatin M (OSM), an interleukin-6 family cytokine, down-regulated the expression of cyclin D1 and D2 in a primary culture of fetal hepatocytes in which OSM induces hepatic differentiation. Ectopic expression of receptor mutants defective in the activation of either STAT3 or SHP-2/Ras indicated that the down-regulation of D1 and D2 cyclins by OSM was mediated by STAT3 but not by SHP-2/Ras. Consistently, expression of dominant negative STAT3 but not Ras relieved OSM-induced suppression of cyclin D expression. Activation of STAT3 in fetal hepatocytes of transgenic mice expressing the STAT3-estrogen receptor fusion protein by 4-hydroxytamoxifen resulted in the suppression of cyclin D1 and D2 expression. These results indicate that STAT3 activation is necessary and sufficient for down-regulation of D1 and D2 cyclins in fetal hepatocytes. Furthermore, STAT3-C, a constitutively active form of STAT3, suppressed transcription of the cyclin D1 promoter in fetal hepatocytes, whereas it activated the transcription in hepatic tumor cells, huH7 and HepG2. Thus, STAT3-mediated down-regulation of cyclin D expression is rather specific to fetal hepatocytes that are undergoing maturation processes including a reduction of their proliferation potential.

  • role of oncostatin m in hematopoiesis and Liver Development
    Cytokine & Growth Factor Reviews, 2000
    Co-Authors: Atsushi Miyajima, Minoru Tanaka, Taisei Kinoshita, Akihide Kamiya, Yousuke Mukouyama, Takahiko Hara
    Abstract:

    Definitive hematopoietic stem cells (HSCs) first appear in the aorta/gonad/mesonephros (AGM) region and migrate to the fetal Liver where they massively produce hematopoietic cells before establishing hematopoiesis in the bone marrow at a perinatal stage. In the AGM region, Oncostatin M (OSM) enhances the Development of both hematopoietic and endothelial cells by possibly stimulating their common precursors, so-called hemangioblasts. During Development of HSCs in the AGM region, the Liver primodium is formed at the foregut and accepts HSCs. While fetal hepatic cells function as hematopoietic microenvironment for expansion of hematopoietic cells during mid to late gestation, they do not possess most of the metabolic functions of adult Liver. Along with the expansion of hematopoietic cells in fetal Liver, OSM is produced by hematopoietic cells and induces differentiation of fetal hepatic cells, conferring various metabolic activities of adult Liver. Matured hepatic cells then lose the ability to support hematopoiesis. Thus, OSM appears to coordinate the Development of Liver and hematopoiesis in the fetus.

Atsushi Suzuki - One of the best experts on this subject based on the ideXlab platform.

  • dynamic three dimensional morphogenesis of intrahepatic bile ducts in mouse Liver Development
    Hepatology, 2015
    Co-Authors: Yasuo Takashima, Maiko Terada, Masuyo Kawabata, Atsushi Suzuki
    Abstract:

    During Liver Development, biliary epithelial cells differentiated from bipotential hepatic progenitor cells (hepatoblasts) form a cell layer, called the ductal plate surrounding portal veins (PVs), and develop into intrahepatic bile ducts (IBDs) following Developmental programs. Because IBDs make duct structures in the Liver, it is necessary to perform sequential and three-dimensional (3D) analyses from the early stages of Liver Development to address the process of morphogenesis in detail. However, to date, the Development of IBDs has mainly been investigated using tissue sections in two-dimensional planes, and examinations of the 3D morphogenesis and quantitative analyses based on morphometrics have not been performed. Therefore, in this study, we simulated the solid structures of IBDs from mouse embryos to adults in silico, analyzed the subjects for the length and number of developing duct structures, number of predicted connections, and discrete distance from the PV, and examined the Developmental process of the IBD in detail in a quantitative manner. Conclusions: Through quantitative analyses with spatiotemporal observations using a 3D structural reconstruction model and morphometrics, we succeeded in constructing a 3D dynamic model of bile duct formation. Because the 3D reconstruction technique used in this study is available for analyzing solid structures in tissues that are difficult to approach, it shows promise for wide use in the fields of biology and medicine. (Hepatology 2015;61:1003–1011)

  • Tbx3 controls the fate of hepatic progenitor cells in Liver Development by suppressing p19ARF expression.
    Development (Cambridge England), 2008
    Co-Authors: Atsushi Suzuki, Sayaka Sekiya, Dirk Büscher, Juan Carlos Izpisua Belmonte, Hideki Taniguchi
    Abstract:

    Although the T-box family of transcription factors function in many different tissues, their role in Liver Development is unknown. Here we show that Tbx3, the T-box gene that is mutated in human ulnar-mammary syndrome, is specifically expressed in multipotent hepatic progenitor cells, ;hepatoblasts', isolated from the developing mouse Liver. Tbx3-deficient hepatoblasts presented severe defects in proliferation as well as uncontrollable hepatobiliary lineage segregation, including the promotion of cholangiocyte (biliary epithelial cell) differentiation, which thereby caused abnormal Liver Development. Deletion of Tbx3 resulted in the increased expression of the tumor suppressor p19(ARF) (Cdkn2a), which in turn induced a growth arrest in hepatoblasts and activated a program of cholangiocyte differentiation. Thus, Tbx3 plays a crucial role in controlling hepatoblast proliferation and cell-fate determination by suppressing p19(ARF) expression and thereby promoting Liver organogenesis.

  • role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells
    Development, 2003
    Co-Authors: Atsushi Suzuki, Hiromitsu Nakauchi, Atsushi Iwama, Hitoshi Miyashita, Hideki Taniguchi
    Abstract:

    In Liver Development, a number of growth factors (GFs) and components of the extracellular matrix (ECMs) lead to differentiation of Liver parenchymal cells. As the Liver contains many cell types, specifically investigating their functional effects on hepatic stem cell populations is difficult. Prospective isolation and clonal assays for hepatic stem cells enable the examination of direct effects of GFs and ECMs on this rare cell fraction. Using previously purified cells that fulfill the criteria for hepatic stem cells, we examined how GFs and ECMs regulate differentiation in the developing Liver. We show here that hepatocyte growth factor (HGF) induced early transition of albumin (ALB)-negative stem cells to ALB-positive hepatic precursors resembling hepatoblasts and then oncostatin M (OSM) promoted their differentiation to tryptophan-2, 3-dioxygenase (TO)-positive mature hepatocytes. During this transition, ECMs were necessary for the differentiation of stem cells and precursors, but their effects were only supportive. In the first step of stem cell differentiation induced by HGF, the expression of CCAAT/enhancer binding protein (C/EBP), a basic leucine zipper transcription factor, changed dramatically. When C/EBP function was inhibited in stem cells, they stopped differentiating to hepatocyte-lineage cells and proliferated actively. These are the first findings to illustrate the mechanism of hepatic stem cell differentiation in Liver Development.