Browsing by Subject "Humanized mice"

Now showing 1 - 3 of 3
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    Expansion, in vivo–ex vivo cycling, and genetic manipulation of primary human hepatocytes
    (National Academy of Sciences, 2020-01-08) Michailidis, Eleftherios; Vercauteren, Koen; Mancio-Silva, Liliana; Andrus, Linda; Jahan, Cyprien; Ricardo-Lax, Inna; Zou, Chenhui; Kabbani, Mohammad; Park, Paul; Quirk, Corrine; Pyrgaki, Christina; Razooky, Brandon; Verhoye, Lieven; Zoluthkin, Irene; Lu, Wei-Yu; Forbes, Stuart J.; Chiriboga, Luis; Theise, Neil D.; Herzog, Roland W.; Suemizu, Hiroshi; Schneider, William M.; Shlomai, Amir; Meuleman, Philip; Bhatia, Sangeeta N.; Rice, Charles M.; de Jong, Ype P.; Pediatrics, School of Medicine
    Primary human hepatocytes (PHHs) are an essential tool for modeling drug metabolism and liver disease. However, variable plating efficiencies, short lifespan in culture, and resistance to genetic manipulation have limited their use. Here, we show that the pyrrolizidine alkaloid retrorsine improves PHH repopulation of chimeric mice on average 10-fold and rescues the ability of even poorly plateable donor hepatocytes to provide cells for subsequent ex vivo cultures. These mouse-passaged (mp) PHH cultures overcome the marked donor-to-donor variability of cryopreserved PHH and remain functional for months as demonstrated by metabolic assays and infection with hepatitis B virus and Plasmodium falciparum. mpPHH can be efficiently genetically modified in culture, mobilized, and then recultured as spheroids or retransplanted to create highly humanized mice that carry a genetically altered hepatocyte graft. Together, these advances provide flexible tools for the study of human liver disease and evaluation of hepatocyte-targeted gene therapy approaches.
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    Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension
    (Frontiers Media, 2022-08-05) Rodriguez-Irizarry, Valerie J.; Schneider, Alina C.; Ahle, Daniel; Smith, Justin M.; Suarez-Martinez, Edu B.; Salazar, Ethan A.; McDaniel Mims, Brianyell; Rasha, Fahmida; Moussa, Hanna; Moustaïd-Moussa, Naima; Pruitt, Kevin; Fonseca, Marcelo; Henriquez, Mauricio; Clauss, Matthias A.; Grisham, Matthew B.; Almodovar, Sharilyn; Medicine, School of Medicine
    People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.
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    Mouse models and human islet transplantation sites for intravital imaging
    (Frontiers Media, 2022-10-05) Wagner, Leslie E.; Melnyk, Olha; Duffett, Bryce E.; Linnemann, Amelia K.; Biochemistry and Molecular Biology, School of Medicine
    Human islet transplantations into rodent models are an essential tool to aid in the development and testing of islet and cellular-based therapies for diabetes prevention and treatment. Through the ability to evaluate human islets in an in vivo setting, these studies allow for experimental approaches to answer questions surrounding normal and disease pathophysiology that cannot be answered using other in vitro and in vivo techniques alone. Intravital microscopy enables imaging of tissues in living organisms with dynamic temporal resolution and can be employed to measure biological processes in transplanted human islets revealing how experimental variables can influence engraftment, and transplant survival and function. A key consideration in experimental design for transplant imaging is the surgical placement site, which is guided by the presence of vasculature to aid in functional engraftment of the islets and promote their survival. Here, we review transplantation sites and mouse models used to study beta cell biology in vivo using intravital microscopy and we highlight fundamental observations made possible using this methodology.