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.

Reply to: “Studies of macrophage therapy for cirrhosis – From mice to men”

“…18 More recently, Merin et al reported that transplanted yolk sacderived Kupffer cells (KCs) exhibited beneficial effects on acetaminophen hepatotoxicity or hepatic ischemia-reperfusion injury. 19 These studies are consistent with the idea that infusion of M1-or M2-polarized macrophages or macrophages with different origin (such as the hepatic resident KCs) might have a different therapeutic output compared to taking the macrophage populations as a whole.…”

Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells

“…Although gene therapy is advancing for hemophilia, cell transplantation will be significant for complex coagulation factor deficiencies, repair of vascular and tissue damage, as well as tissue engineering and neoorganogenesis. As multiple cell types may be transplanted simultaneously to reconstitute the liver, including hepatocytes, LSEC, KC, and HSC, 12,55 cell interactions may be studied in vivo. These studies of cell interactions will be advanced by efficient engraftment and proliferation of co-transplanted cells with the mechanism of ET A/B antagonism.…”

“…As engraftment in liver of transplanted KC is inefficient and these do not proliferate, their presence was inconsequential. 12 ET A/B receptor antagonism by BOS and time-to-transplantation…”

“…2,[7][8][9] Major roles of LSEC include support of hepatic development, homeostasis, and regeneration, [9][10][11] and their losses in adult liver due to injury or inflammation during the course of diseases is harmful. 2,4,12,13 Injuries in LSEC may also arise due to anticancer or other drugs, toxins, and radiation. Such vascular damage may be restrictive for completing (cancer) therapies and might lead to disabling liver conditions (e.g., sinu-soidal obstruction syndrome).…”

Cholesterol metabolism and statin effects on an FH class II LDL-receptor mutation.

“…Because of this, cultured hepatocytes begin to dedifferentiate and lose their polarity over a short time. An additional key factor that has limited the application of hepatocyte transplantation is the significant cell loss posttransplantation [266,267,[273][274][275][276][277][278][279]. Without immunosuppressive drugs, transplanted allogeneic hepatocytes survive for only 7 to 10 days [258,267,280].…”