title: Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice.
abstract: Human-specific HIV-1 and hepatitis co-infections significantly affect patient management and call for new therapeutic options. Small xenotransplantation models with human hepatocytes and hematolymphoid tissue should facilitate antiviral/antiretroviral drug trials. However, experience with mouse strains tested for dual reconstitution is limited, with technical difficulties such as risky manipulations with newborns and high mortality rates due to metabolic abnormalities. The best animal strains for hepatocyte transplantation are not optimal for human hematopoietic stem cell (HSC) engraftment, and vice versa. We evaluated a new strain of highly immunodeficient nonobese diabetic/Shi-scid (severe combined immunodeficiency)/IL-2Rγc(null) (NOG) mice that carry two copies of the mouse albumin promoter-driven urokinase-type plasminogen activator transgene for dual reconstitution with human liver and immune cells. Three approaches for dual reconstitution were evaluated: i) freshly isolated fetal hepatoblasts were injected intrasplenically, followed by transplantation of cryopreserved HSCs obtained from the same tissue samples 1 month later after treosulfan conditioning; ii) treosulfan conditioning is followed by intrasplenic simultaneous transplantation of fetal hepatoblasts and HSCs; and iii) transplantation of mature hepatocytes is followed by mismatched HSCs. The long-term dual reconstitution was achieved on urokinase-type plasminogen activator-NOG mice with mature hepatocytes (not fetal hepatoblasts) and HSCs. Even major histocompatibility complex mismatched transplantation was sustained without any evidence of hepatocyte rejection by the human immune system.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Tanuja L
authors.initials: TL
authors.lastname: Gutti
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Jaclyn S
authors.initials: JS
authors.lastname: Knibbe
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Edward
authors.initials: E
authors.lastname: Makarov
authors.affiliation: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Govardhana R
authors.initials: GR
authors.lastname: Yannam
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: David F
authors.initials: DF
authors.lastname: Mercer
authors.affiliation: Laboratory Animal Research Department, Central Institute for Experimental Animals, Kanagawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suemizu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: James L
authors.initials: JL
authors.lastname: Wisecarver
authors.affiliation: Liver Unit, Nebraska/Western Iowa Healthcare System, Omaha, Nebraska.
authors.forename: Natalia A
authors.initials: NA
authors.lastname: Osna
authors.affiliation: Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Tatiana K
authors.initials: TK
authors.lastname: Bronich
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska; Liver Unit, Nebraska/Western Iowa Healthcare System, Omaha, Nebraska. Electronic address: lpoluekt@unmc.edu.
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002066:Busulfan / Q000031:analogs & derivatives / Q000494:pharmacology; D060085:Coinfection; D004195:Disease Models, Animal; D015658:HIV Infections; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006526:Hepatitis C; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D019076:Transgenes; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; C018404:treosulfan; D014568:Urokinase-Type Plasminogen Activator; D002066:Busulfan