Embryonic Mouse STO Cell–Derived Xenografts Express Hepatocytic Functions in the Livers of Nonimmunosuppressed Adult Rats

Abstract

Cells derived from embryonic mouse STO cell lines differentiate into hepatocytes when transplanted into the livers of nonimmunosuppressed dipeptidylpeptidase IV (DPPIV)-negative F344 rats. Within 1 day after intrasplenic injection, donor cells moved rapidly into the liver and were found in intravascular and perivascular sites; by 1 month, they were intrasinusoidal and also integrated into hepatic plates with approximately 2% efficiency and formed conjoint bile canaliculi. Neither donor cell proliferation nor host inflammatory responses were observed during this time. Detection of intrahepatic mouse COX1 mitochondrial DNA and mouse albumin mRNA in recipient rats indicated survival and differentiation of donor cells for at least 3 months. Mouse COX1 targets were also detected intrahepatically 4-9 weeks after STO cell injection into nonimmunosuppressed wild-type rats. In contrast to STO-transplanted rats, mouse DNA or RNA was not detectable in untreated or mock-transplanted rats or in rats injected with donor cell DNA. In cultured STO donor cells, DPPIV and glucose-6-phosphatase activities were observed in small clusters; in contrast, mouse major histocompatibility complex class I H-2Kq , H-2D q , and H-2L q and class II I-A q markers were undetectable in vitro before or after interferon gamma treatment. Together with H-2K allele typing, which confirmed the Swiss mouse origin of the donor cells, these observations indicate that mouse-derived STO cell lines can differentiate along hepatocytic lineage and engraft into rat liver across major histocompatibility barriers.

Embryonic Stem Cell-Derived Factors Inhibit T Effector Activation and Induce T Regulatory Cells by Suppressing PKC-θ Activation

“…Several groups have demonstrated that ESCs have immune modulatory properties that not only allow ESCs to survive across allogeneic immune barrier but also provide protection to solid organ transplants [5], [10], [12], [13], [14], [15], [17], [18], [19], [20], [22], [40], [41]. Here we have further demonstrated that ESCs have the capacity to directly inhibit T cell proliferation and activation.…”

“…These properties allow ESCs to survive across both allogeneic and xenogeneic barriers without evoking immune responses [10], [11], [12], [13], [14], [15], [16], [17], [18], [19]. The ability of ESCs to evade the immune system may be associated with their very low level of MHC I expression and no MHC II expression [10], [11], [12], [14], [15], [16].…”

Human Embryonic Stem Cell-extracts Inhibit the Differentiation and Function of Monocyte-derived Dendritic Cells

“…Interestingly, hESCs also possess properties of immune privilege similar to fetal tissues during pregnancy [13][14][15][16][17][18][19][20]. Specifically, hESCs seem to be non-immunogenic and do not elicit immune responses in the presence of allogeneic immune cells and can persist across allogeneic and even xenogeneic barriers [14,15,17,18,[21][22][23]. This property has been attributed to very low levels of MHC I expression and absence of MHC II, CD80, CD86 and CD40L [13,17].…”

Immune‐privileged embryonic Swiss mouse STO and STO cell‐derived progenitor cells: major histocompatibility complex and cell differentiation antigen expression patterns resemble those of human embryonic stem cell lines

“…For example, human embryonic stem (hES) cell lines, generated either by somatic cell nuclear transfer (SCNT) in enucleated human oocytes or by fusion and reprogramming of adult somatic cells, have been proposed as sources of patient‐ and organ‐specific donor cells 14–17 . Although the engraftment and functional properties of cloned and reprogrammed ES and SCNT cells have yet to be demonstrated, transplantation studies with conventional hES and non‐human stem, MSC or progenitor cell systems in non‐immunosuppressed hosts have been described 18–24 . Properties of this group of immune‐privileged systems, summarized in Table 1, suggest the following trends: firstly, the incidence of class I [LOW] expression is higher than that of non‐expression; secondly, none of the cells expresses MHC/human leucocyte antigen (HLA) class II determinants; thirdly, graft survival times vary markedly, from 2 to 90 days; and, lastly, common patterns and mechanisms of intrinsic immune privilege have not yet emerged 18–25 .…”

“…Although the engraftment and functional properties of cloned and reprogrammed ES and SCNT cells have yet to be demonstrated, transplantation studies with conventional hES and non‐human stem, MSC or progenitor cell systems in non‐immunosuppressed hosts have been described 18–24 . Properties of this group of immune‐privileged systems, summarized in Table 1, suggest the following trends: firstly, the incidence of class I [LOW] expression is higher than that of non‐expression; secondly, none of the cells expresses MHC/human leucocyte antigen (HLA) class II determinants; thirdly, graft survival times vary markedly, from 2 to 90 days; and, lastly, common patterns and mechanisms of intrinsic immune privilege have not yet emerged 18–25 . Furthermore, the biological status of the xenogeneic and allogeneic grafts in several reported situations is questionable: 18–22 for example, potential artifacts caused by unwanted donor cell fusion with recipient cells, 26–29 by genomically integrated vectors and reporter genes, or by transfection of recipient cells with naked DNA released from dying donor cells have yet to be eliminated; in one investigation, primary data were lacking 22 …”