Embryonic Porcine Liver as a Source for Transplantation: Advantage of Intact Liver Implants over Isolated Hepatoblasts in Overcoming Homeostatic Inhibition by the Quiescent Host Liver

Abstract

Cell therapy as an alternative to orthotopic liver transplantation represents a major challenge, since negligible proliferation of isolated hepatocytes occurs after transplantation because of the stringent homeostatic control displayed by the host liver. Thus, different modalities of liver injury as part of the pretransplant conditioning are a prerequisite for this approach. The major objective of the present study was to test whether xenotransplantation of pig fetal liver fragments, in which potential cell-cell and cell-stroma interactions are spared, might afford more robust growth and proliferation compared with isolated pig fetal hepatoblasts. After transplantation into SCID mice, fetal liver tissue fragments exhibited marked growth and proliferation, in the setting of a quiescent host liver, compared with isolated fetal hepatoblasts harvested at the same gestational age (embryonic day 28). The proliferative advantage of fetal pig liver fragments was clearly demonstrated by immunohistochemical and morphometric assays and was observed not only after implantation into the liver but also into extrahepatic sites, such as the spleen and the subrenal capsule. The presence of all types of nonparenchymal liver cells that is crucial for normal liver development and regeneration was demonstrated in the implants. Preservation of the three-dimensional structure in pig fetal liver fragments enables autonomous proliferation of transplanted hepatic cells in the setting of a quiescent host liver, without any requirement for liver injury in the pretransplant conditioning. The marked proliferation and functional maturation exhibited by the pig fetal liver fragments suggests that it could afford a preferable source for transplantation. STEM CELLS 2008;

Cryo-chemical decellularization of the whole liver for mesenchymal stem cells-based functional hepatic tissue engineering

“…Previous studies have indicated that hepatic progenitor cells (or fetal liver cells) possess greater regenerate potential than fully matured hepatocytes in experimental liver failure models [34,35]; therefore, MSCs may be a better source for HLT compared to mature hepatocytes. It have also been shown that transplantation of fetal liver fragments or implants are functional at the intrahepatic implantation site [36]. Our findings clearly indicate that orthotopic intrahepatic transplantation of HLT in vivo can not only preserve liver function but can also potentially contribute to the restoration of liver function in the animal model of lethal fulminant hepatic failure (Fig.…”

Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice

“…We have shown previously that embryonic progenitor tissues of different organs have distinct gestational 'windows' for harvesting optimal regenerative tissue for transplantation [13][14][15][16][17][18] . To evaluate a suitable window for human fetal lung progenitors, we initially characterized the growth and differentiation potential of lung precursor tissues harvested at different gestational time points.…”

“…Transplantation of the embryonic precursor tissues was performed on mice under general anesthesia (2.5% 2,2,2-tribromoethanol in PBS, 10 ml per kg of body weight (mg/kg) administered intraperitoneally) as previously described [13][14][15][16][17] .…”

Embryonic Porcine Skin Precursors Can Successfully Develop into Integrated Skin without Teratoma Formation Posttransplantation in Nude Mouse Model

“…Interestingly, a recent series of studies demonstrated that grafting embryonic tissue or organ precursors could successfully generate the wanted tissues or organs without the risk of teratoma formation[7], [8], [9], [13], [14], [15], [16]. This strategy overcomes both the difficulties of precise control of stem cell differentiation and the formation of 3 dimensional structures of a tissue or an organ.…”