Kupffer Cell Transplantation in Mice for Elucidating Monocyte/Macrophage Biology and for Potential in Cell or Gene Therapy

• Published in: The American journal of pathology Vol. 186; no. 3; pp. 539 - 551
• Main Authors: Merlin, Simone, Bhargava, Kuldeep K, Ranaldo, Gabriella, Zanolini, Diego, Palestro, Christopher J, Santambrogio, Laura, Prat, Maria, Follenzi, Antonia, Gupta, Sanjeev
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2016; American Society for Investigative Pathology
• Subjects: Acetaminophen - adverse effects; Animals; Chemical and Drug Induced Liver Injury - pathology; Cytokines - metabolism; Disease Models, Animal; Gadolinium; Genetic Therapy; Humans; Kupffer Cells - physiology; Kupffer Cells - transplantation; Liver - metabolism; Macrophages - physiology; Male; Mice; Mice, Inbred C57BL; Monocytes - physiology; Pathology; Phagocytosis; Regular; Reperfusion Injury - metabolism; Reperfusion Injury - therapy; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2015.11.002

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.