title: Kupffer Cell Transplantation in Mice for Elucidating Monocyte/Macrophage Biology and for Potential in Cell or Gene Therapy.
abstract: Kupffer cells (KC) play major roles in immunity and tissue injury or repair. Because recapitulation of KC biology and function within liver will allow superior insights into their functional repertoire, we studied the efficacy of the cell transplantation approach for this purpose. Mouse KC were isolated from donor livers, characterized, and transplanted into syngeneic recipients. To promote cell engraftment through impairments in native KC, recipients were preconditioned with gadolinium chloride. The targeting, fate, and functionality of transplanted cells were evaluated. The findings indicated that transplanted KC engrafted and survived in recipient livers throughout the study period of 3 months. Transplanted KC expressed macrophage functions, including phagocytosis and cytokine expression, with or without genetic modifications using lentiviral vectors. This permitted studies of whether transplanted KC could affect outcomes in the context of acetaminophen hepatotoxicity or hepatic ischemia-reperfusion injury. Transplanted KC exerted beneficial effects in these injury settings. The benefits resulted from cytoprotective factors including vascular endothelial growth factor. In conclusion, transplanted adult KC were successfully targeted and engrafted in the liver with retention of innate immune and tissue repair functions over the long term. This will provide excellent opportunities to address critical aspects in the biogenesis, fate, and function of KC within their native liver microenvironment and to develop the cell and gene therapy potential of KC transplantation.
authors.affiliation: Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Merlin
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, North Shore - Long Island Jewish Health System, New Hyde Park, New York.
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Bhargava
authors.affiliation: Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ranaldo
authors.affiliation: Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Zanolini
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, North Shore - Long Island Jewish Health System, New Hyde Park, New York.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Palestro
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
authors.affiliation: Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Prat
authors.affiliation: Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy; Department of Pathology, Albert Einstein College of Medicine, Bronx, New York. Electronic address: antonia.follenzi@med.uniupo.it.
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; Department of Medicine, Marion Bessin Liver Research Center, Cancer Research Center, Diabetes Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, and Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, New York. Electronic address: sanjeev.gupta@einstein.yu.edu.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005682:Gadolinium; D015316:Genetic Therapy; D006801:Humans; D007728:Kupffer Cells / Q000502:physiology* / Q000637:transplantation*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology; D010587:Phagocytosis; D015427:Reperfusion Injury / Q000378:metabolism / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016207:Cytokines; D042461:Vascular Endothelial Growth Factor A; D000082:Acetaminophen; D005682:Gadolinium; C038958:gadolinium chloride