The long-term objectives of this R21 application are to characterize several key biological and immunological properties of embryonic Swiss mouse STO- and STO cell-derived (SCO) progenitor cell lines to determine the utility of these cells as novel model systems of progenitor cell differentiation and engraftment into non- immunosuppressed mammalian hosts. Intrahepatic xenografts of STO and SCO cell lines survive without immunosuppression for at least three months in either dipeptidylpeptidase IV-negative (DPPIV) German F344 rats or in their wild type DPPIV* counterparts. An EGFP-labeled SCO cell line (3(8)21-EGFP) also survives without immunosuppression for at least one month as a subcapsular renal allograft in adult C57BL/6J mice, and as a subdural xenograft in C3-lesioned spinal cords in adult F344 rats. Donor mouse STO and SCO cells display phenotypes (MHC class I+[LOW1 (H-2Kd[LOW]) / class ll-negative (l-AdH); CD80- and CD86-negative) consistent with immune privilege; they differentiate into hepatic and axon-inducing neuroglial lineages in the rat liver and lesioned rat spinal cord models in vivo, respectively, and into duct-like structures under mouse renal capsules. These novel and unexpected findings suggest the hypothesis that STO and SCO cells might provide immune-privileged pluripotential progenitor cell-like material for universal tissue grafts in non-immunosuppressed recipients. Accordingly, STO and SCD cells will be used to: 1] investigate in vitro hepatocytic progenitor cell potential; 2] investigate in vivo hepatocytic progenitor cell potential and allogeneic survival in non-immunosuppressed wild type and genetically injured knockout and transgenic H-2b mice; 3] characterize immunogenicity and antigenicity in non-immunosuppressed allogeneic mice; and, 4] delineate mechanisms of non-expression of costimulatory molecules CD80 and CD86. Standard procedures of cell and molecular biology, biochemistry, immunology, transplantation and mouse genetics will be exploited, along with real-time EGFP imaging. The properties of the donor cells and recipient models examined thus far suggest novel possibilities for developing nonhuman sources of immune privileged progenitor cells for transplantation without immunosuppression. As a result of these proposed studies, new cellular reagents will be available for new models for regenerative and transplantation medicine. ? ? ?
| Koch, Katherine S; Leffert, Hyam L (2011) Ectopic expression of CD74 in Ikk?-deleted mouse hepatocytes. Acta Histochem 113:428-35 |
| Koch, Katherine S; Leffert, Hyam L (2010) Hypothesis: Targeted Ikk? deletion upregulates MIF signaling responsiveness and MHC class II expression in mouse hepatocytes. Hepat Med 2010:39-47 |
| He, Guobin; Yu, Guann-Yi; Temkin, Vladislav et al. (2010) Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17:286-97 |
| Koch, Katherine S; Maeda, Shin; He, Guobin et al. (2009) Targeted deletion of hepatocyte Ikkbeta confers growth advantages. Biochem Biophys Res Commun 380:349-54 |
| Sell, Stewart; Leffert, Hyam L (2008) Liver cancer stem cells. J Clin Oncol 26:2800-5 |
