Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator

Heckel, Janice L.; Sandgren, Eric P.; Degen, Jay L.; Palmiter, Richard D.; Brinster, Ralph L.

doi:10.1016/0092-8674(90)90010-c

Cited by 204 publications

(154 citation statements)

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“…The 1944-6 line of AL-uPA transgenic mice used in these studies was described previously, 34,35 and has been assigned the following genetic designation: Tg(Alb-1 Plau)145Bri. Mice heterozygous for the transgene were used in this study.…”

Section: Transgenic Micementioning

confidence: 99%

“…9,13,24,32,33 Transgenic mice in which urokinase-type plasminogen activator (uPA) expression is targeted to hepatocytes develop hepatocellular disease. 34,35 Young albumin (AL)-uPA transgenic mouse liver appears pale compared to nontransgenic littermate liver, and hepatocytes contain rough endoplasmic reticulum vacuolations. Beginning at ϳ2 weeks of age, red foci of hepatocytes become visible in the transgenic liver; these foci gradually expand until the pale areas are replaced by confluent red nodules.…”

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confidence: 99%

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Hepatic Microenvironment Affects Oval Cell Localization in Albumin-Urokinase-Type Plasminogen Activator Transgenic Mice

Braun

Thompson

Sandgren

2003

The American Journal of Pathology

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Mice carrying an albumin-urokinase type plasminogen activator transgene (AL-uPA) develop liver disease secondary to uPA expression in hepatocytes. Transgene-expressing parenchyma is replaced gradually by clones of cells that have deleted transgene DNA and therefore are not subject to uPA-mediated damage. Diseased liver displays several abnormalities, including hepatocyte vacuolation and changes in nonparenchymal tissue. The latter includes increases in laminin protein within parenchyma and the appearance of cytokeratin 19-positive bile ductule-like cells (oval cells) both in portal regions and extending into the hepatic parenchyma. In this study, we subjected ALuPA mice to two-thirds partial hepatectomy to identify the response of these livers to additional growth stimulation. We observed several changes in hepatic morphology. First, the oval cells increased in number and often formed ductules in the parenchyma. Second, this cellular change was accompanied by a further increase in laminin associated with single or clusters of oval cells. Third, desmin-positive Ito cells increased in number and maintained close association with oval cells. Fourth, these changes were localized precisely to uPA-expressing areas of liver. Regenerating clones of uPA-deficient cells appeared to be unaffected both by stromal and cellular alterations. Thus, additional growth stimulation of diseased uPAexpressing liver induces an oval cell-like response, as observed in other models of severe hepatic injury, but the localization of this response seems to be highly regulated by the hepatic microenvironment.

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Section: Transgenic Micementioning

confidence: 99%

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confidence: 99%

Hepatic Microenvironment Affects Oval Cell Localization in Albumin-Urokinase-Type Plasminogen Activator Transgenic Mice

Braun

Thompson

Sandgren

2003

The American Journal of Pathology

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“…An environment that favors hepatocyte engraftment is encountered in animals with severe, chronic liver disease caused by the overexpression of a "noxious" protein, as in the urokinase plasminogen activator (uPA)-transgenic mouse. 4 uPA transgenic mice backcrossed with "severe immune deficient" mice, such as Swiss athymic nude (nu/nu) mice, 5 recombination activation gene 2 (RAG-2) knockout mice, 6,7 or SCID/beige mice, 8 allow the engraftment and repopulation by xenogeneic hepatocytes.…”

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Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera

et al. 2005

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D espite decades of research, the processes that govern liver development and regeneration are only partially understood. A good understanding of the mechanisms that play a role in these processes is important because it may lead to new treatments of human liver diseases. Several in vivo experimental conditions have been used to study liver regeneration and repair and the interaction of different cell types in these processes. These include partial hepatectomy, administration of toxic compounds, or a combination of both, and transgenic expression of certain proteins. 1,2 In contrast to in vitro experiments, these approaches raise fewer questions concerning the influence of artificial matrices on the function and behavior of hepatocytes and other liver cell types.Although these procedures have generated useful information on rodent liver regeneration, stem cell activation, and other processes, extrapolating these findings to the Abbreviations: uPA, urokinase plasminogen activator; HBV, hepatitis B virus; HCV, hepatitis C virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen; PAS, periodic-acid-Schiff. From the

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“…Almost 20 years ago, a murine model was described in which overexpression of a urokinase plasminogen activator (uPA) transgene resulted not only in neonatal bleeding disorders, but also in severe liver toxicity. 69 Importantly, the diseased liver could be replaced by donor hepatocytes of murine origin, as well as by hepatocytes from rats, woodchucks, and humans once the uPA transgenic mice were backcrossed on an immunodeficient background. Human hepatocytes integrated themselves in the murine liver and formed organized nodules.…”

Section: Small-animal Models For Hcv Infectionmentioning

confidence: 99%

Experimental models for hepatitis C viral infection

Boonstra¹,

Laan²,

Vanwolleghem³

et al. 2009

Hepatology

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Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The majority of infected individuals develop a persistent infection, which is associated with a high risk of liver cirrhosis and hepatocellular carcinoma. Since its discovery 20 years ago, progress in our understanding of this virus has been suboptimal due to the lack of good model systems. However, in the past decade this has greatly accelerated with the development of various in vitro cell culture systems and in vivo small-animal models. These systems have made a major impact on the field of HCV research, and have provided important breakthroughs in our understanding of HCV infection and replication. Importantly, the in vitro cell culture systems and the small-animal models have allowed preclinical testing of numerous novel antiviral compounds for the treatment of chronic HCV infection. In this article, we give an overview of current models, discuss their limitations, and provide future perspectives for research directed at the prevention and cure of hepatitis C. (HEPATOLOGY 2009;50:1646-1655.) Hepatitis C Virus Pathology and BiologyThe hepatitis C virus (HCV) is considered a successful pathogen in establishing persistent infections by evading the immune system. Only a fraction of acutely infected individuals are able to clear the infection spontaneously, whereas about 80% of the infected individuals develop a chronic infection. 1,2 The symptoms are initially mild in these persistently infected patients, and it may take decades before the serious consequences of chronic HCV infection become apparent. Patients with chronic HCV are at increased risk for developing liver fibrosis, cirrhosis, and/or hepatocellular carcinoma. Currently, these longterm complications of chronic HCV infection are the leading indication for liver transplantation. 3,4 Because of the high incidence of new infections by blood transfusions in the 1980s before discovery of the virus, and because morbidity associated with chronic HCV infections generally takes decades to develop, it is expected that the burden of disease in the near future will rise dramatically.HCV is an enveloped flavivirus, with a positivestranded RNA genome of approximately 9600 nucleotides and is composed of a single open reading frame, which encodes a polyprotein precursor of approximately 3000 amino acids. The coding region is flanked by 5Ј and 3Ј noncoding regions, which are important for the regulation of genomic duplication as well as initiation of translation. The single polyprotein is cleaved by host and viral proteases into individual structural and nonstructural (NS) proteins (Fig. 1A). Replication of the HCV genome involves the synthesis of a full-length negative-stranded RNA intermediate, which in turn provides a template for the de novo production of positive-stranded RNA. Both these synthesis steps are mediated by the viral RNA-dependent RNA polymerase NS5B. 5-7 NS5B lacks proofreading abilities, and this leads to a high mutation rate and the generation of numerous quasispecies. ...

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Neonatal bleeding in transgenic mice expressing urokinase-type plasminogen activator

Cited by 204 publications

References 33 publications

Hepatic Microenvironment Affects Oval Cell Localization in Albumin-Urokinase-Type Plasminogen Activator Transgenic Mice

Hepatic Microenvironment Affects Oval Cell Localization in Albumin-Urokinase-Type Plasminogen Activator Transgenic Mice

Morphological and biochemical characterization of a human liver in a uPA-SCID mouse chimera

Experimental models for hepatitis C viral infection

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