Abstract
The liver is the largest internal organ and the center of homeostatic metabolism. Liver-directed cell transplantation is, therefore, an attractive therapeutic option to treat various metabolic disorders as well as liver diseases. Although clinical liver-directed cell transplantation requires multiple cell injections into the portal venous system, a mouse model is lacking which allows us to perform repetitive cell injections into the portal venous system. Here, we propose a surgical model that utilizes the spleen as a subcutaneous injection port. Mouse spleens were translocated under the skin with intact vascular pedicles. Human placental stem cell transplantations were performed one week following this port construction and repeated three times. Cell distribution was analyzed by quantifying human DNA using human Alu-specific primers. About 50% of the transplanted cells were located homogeneously in the liver one hour after the splenic port injection. Fluorescent-labeled cell tracking and antihuman mitochondrion immunohistochemistry studies demonstrated that the cells localized predominantly in small distal portal branches. A similar cell distribution was observed after multiple cell injections. These data confirm that the subcutaneous splenic injection port is suitable for performing repetitive cell transplantation into the portal venous system of mouse models.
Highlights
Hepatocyte transplantation is one of the promising regenerative approaches for the restoration of or compensation for impaired liver functions [1,2,3]
The therapeutic efficacy of this approach has been demonstrated in over 100 clinical trials, limited availability of the human hepatocyte prohibits the use of this therapeutic option for patients with liver diseases ranging from congenital metabolic disorders to liver cirrhosis [4, 5]
Direct liver injection can be used in hairless neonatal mouse models, the direct liver injection approach cannot avoid the possibility of injecting cells into the hepatic venous system, and obtaining hemostasis can be difficult
Summary
Hepatocyte transplantation is one of the promising regenerative approaches for the restoration of or compensation for impaired liver functions [1,2,3]. When used clinically for the treatment of human disease, hepatocytes are transplanted multiple times into the portal circulation in order to obtain a therapeutic dose This is accomplished via a catheter placed in either the intrahepatic portal vein, the middle colic vein, the inferior mesenteric vein, or the patent umbilical vein in the case of neonatal recipients. Direct liver injection can be used in hairless neonatal mouse models, the direct liver injection approach cannot avoid the possibility of injecting cells into the hepatic venous system, and obtaining hemostasis can be difficult. This makes intrasplenic cell injection the current “gold standard” procedure for cell transplantation in rodent models
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