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Hepatic progenitor/oval cells appear in injured livers when hepatocyte proliferation is impaired. These cells can differentiate into hepatocytes and cholangiocytes and could be useful for cell and gene therapy applications. In this work, we studied progenitor/oval cell surface markers in the liver of rats subjected to 2-acetylaminofluorene treatment followed by partial hepatectomy (2-AAF/PH) by using rat

Background & Aims-Hepatocyte transplantation-induced liver inflammation impairs cell engraftment. We defined whether proinflammatory cytokines and chemokines played roles in regulation of hepatocyte engraftment in the liver.

Summary.  Background: The deficiency of factor VIII, a co‐factor in the intrinsic coagulation pathway results in hemophilia A. Although FVIII is synthesized largely in the liver, the specific liver cell type(s) responsible for FVIII production is controversial. Objective: This study aimed to determine the cellular origin of FVIII synthesis and release in mouse models. Methods: We transplanted cells into the peritoneal cavity of hemophilia A knockout mice. Plasma FVIII activity was measured using a Chromogenix assay 2–7 days after cell transplantation, and phenotypic correction was determined with tail‐clip challenge 7 days following cell transplantation. Transplanted cells were identified by histologic and molecular assays. Results: Untreated hemophilia A mice, as well as mice treated with the hepatocyte‐enriched fraction, showed extensive mortality following tail‐clip challenge. In contrast, recipients of unfractionated liver cells (mixture of hepatocytes, liver sinusoidal endothelial cells (LSEC), Kupffer cells, and hepatic stellate cells) or of the cell fraction enriched in LSECs survived tail‐clip challenge (P < 0.001). FVIII was secreted in the blood stream in recipients of unfractionated liver cells, LSECs and pancreatic islet‐derived MILE SVEN 1 (MS1) endothelial cells. Although transplanted hepatocytes maintained functional integrity in the peritoneal cavity, these cells did not produce detectable plasma FVIII activity. Conclusions: The assay of cell transplantation in the peritoneal cavity showed that endothelial cells but not hepatocytes produced phenotypic correction in hemophilia A mice. Therefore, endothelial cells should be suitable additional targets for cell and gene therapy in hemophilia A.

The potential for organ damage after using drugs or chemicals is a critical issue in medicine. To delineate mechanisms of drug-induced hepatic injury, we used transplanted cells as reporters in dipeptidyl peptidase IV-deficient mice. These mice were given phenytoin and rifampicin for 3 days, after which monocrotaline was given followed 1 day later by intrasplenic transplantation of healthy C57BL/6 mouse hepatocytes. We examined endothelial and hepatic damage by serologic or tissue studies and assessed changes in transplanted cell engraftment and liver repopulation by histochemical staining for dipeptidyl peptidase IV. Monocrotaline caused denudation of the hepatic sinusoidal endothelium and increased serum hyaluronic acid levels, along with superior transplanted cell engraftment. Together, phenytoin, rifampicin, and monocrotaline caused further endothelial damage, reflected by greater improvement in cell engraftment. Phenytoin, rifampicin, and monocrotaline produced injury in hepatocytes that was not apparent after conventional tissue studies. This led to transplanted cell proliferation and extensive liver repopulation over several weeks, which was more efficient in males compared with females, including greater induction by phenytoin and rifampicin of cytochrome P450 3A4 isoform that converts monocrotaline to toxic intermediates. Through this and other possible mechanisms, monocrotaline-induced injury in the endothelial compartment was retargeted to simultaneously involve hepatocytes over the long term. Moreover, after this hepatic injury, native liver cells were more susceptible to additional pro-oxidant injury through thyroid hormone, which accelerated the kinetics of liver repopulation. Conclusion: Transplanted reporter cells will be useful for obtaining insights into homeostatic mechanisms involving liver cell compartments, whereas targeted injury in hepatic endothelial and parenchymal cells with suitable drugs will also help advance liver cell therapy. ( T o obtain fresh paradigms in tissue homeostasis after exposure to drugs or chemicals, 1 we considered that reporter cells will help elucidate perturbations in the liver, because genetically marked reporter cells can be inserted into liver compartments, including the parenchyma or hepatic endothelium. 2-4 It was noteworthy that transplanted cells did not proliferate in the normal liver, where cell turnover is minimal, although, depending on the extent of injury in native cells, proliferation in healthy transplanted cells was activated. 5,6 In this way, transplanted cells could repopulate the liver, where in specific situations the kinetics of liver repopulation reflected loss of native hepatocytes. [7][8][9] In healthy animals, genotoxic manipulations were particularly effective in promoting such liver repopulation with healthy cells. However, further insights are necessary to obtain pharmacologic approaches for repopulating the liver, particularly for clinical applications.To develop cell compartment-specific hepatic perturbations, we used monocrotaline (...