Properties of Immune-Privileged STO-Progenitor Cells

描述（由申请人提供）：本R21申请的长期目标是表征胚胎瑞士小鼠STO和STO细胞衍生（SCO）祖细胞系的几种关键生物学和免疫学特性，以确定这些细胞作为祖细胞分化和植入非免疫抑制哺乳动物宿主的新型模型系统的效用。STO和SCO细胞系的肝内异种移植物在没有免疫抑制的情况下在二肽基肽酶IV阴性（DPPIV）德国F344大鼠或其野生型DPPIV* 对应物中存活至少3个月。EGFP标记的SCO细胞系（3（8）21-EGFP）也在没有免疫抑制的情况下作为成年C57 BL/6 J小鼠的被膜下肾同种异体移植物和作为成年F344大鼠的C3损伤脊髓中的硬膜下异种移植物存活至少一个月。供体小鼠STO和SCO细胞显示与免疫赦免一致的表型（MHC I类+[LOW 1（H-2Kd[LOW]）/II类阴性（l-AdH）; CD 80-和CD 86-阴性）;它们分别在大鼠肝脏和损伤的大鼠脊髓模型中分化成肝脏和轴突诱导的神经胶质细胞谱系，并在小鼠肾包膜下分化成导管样结构。这些新的和意想不到的发现表明，假设STO和SCO细胞可能提供免疫特权的多能祖细胞样材料的通用组织移植在非免疫抑制受体。因此，STO和SCD细胞将用于：1）研究体外肝细胞祖细胞潜能; 2）研究非免疫抑制的野生型和遗传损伤的敲除和转基因H-2b小鼠中的体内肝细胞祖细胞潜能和同种异体存活; 3）表征非免疫抑制的同种异体小鼠中的免疫原性和抗原性;和，4]描绘了共刺激分子CD 80和CD 86不表达的机制。细胞和分子生物学，生物化学，免疫学，移植和小鼠遗传学的标准程序将被利用，沿着实时EGFP成像。到目前为止检查的供体细胞和受体模型的性质表明，开发非人类来源的免疫豁免祖细胞移植无免疫抑制的新的可能性。由于这些拟议的研究，新的细胞试剂将可用于再生和移植医学的新模型。

DESCRIPTION (provided by applicant): 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.