Embryonic pig liver, pancreas, and lung as a source for transplantation: Optimal organogenesis without teratoma depends on distinct time windows

Abstract

Pig embryonic tissues represent an attractive option for organ transplantation. However, the achievement of optimal organogenesis after transplantation, namely, maximal organ growth and function without teratoma development, represents a major challenge. In this study, we determined distinct gestational time windows for the growth of pig embryonic liver, pancreas, and lung precursors. Transplantation of embryonic-tissue precursors at various gestational ages [from E (embryonic day) 21 to E100] revealed a unique pattern of growth and differentiation for each embryonic organ. Maximal liver growth and function were achieved at the earliest teratoma-free gestational age (E28), whereas the growth and functional potential of the pancreas gradually increased toward E42 and E56 followed by a marked decline in insulin-secreting capacity at E80 and E100. Development of mature lung tissue containing essential respiratory system elements was observed at a relatively late gestational age (E56). These findings, showing distinct, optimal gestational time windows for transplantation of embryonic pig liver, pancreas, and lung, might explain, in part, the disappointing results in previous transplantation trials and could help enhance the chances for successful implementation of embryonic pig tissue in the treatment of a wide spectrum of human diseases.fetal ͉ porcine ͉ gestational age ͉ growth potential

Reduced Immunogenicity of First-Trimester Human Fetal Pancreas

“…Similar results have been shown in xenograft transplantations of fetal pig pancreas into humanized mice. Pancreatic tissue from embryonic day 42, which corresponds to early second-trimester tissue, showed markedly reduced immunogenicity compared with older tissue, was able to normalize BGLs in diabetic mice, and exhibited superior insulin secretion and growth after transplantation compared with younger tissue (16,31). This demonstrates that tissues from specific windows of gestational development are more suitable for transplantation than others.…”

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model

“…We have shown recently in a mouse model that this outcome could be attributed, in part, to the relatively late stage of gestation at which the embryonic pancreatic tissue was harvested. Thus, based on growth potential and immunogenicity, we demonstrated that the optimal ''window'' for these transplants could be provided at around E42 (7,9).…”

“…One means to address this challenge could be provided by the use of embryonic porcine tissue. This strategy is based on the growing evidence, over the past 5 decades, demonstrating maternal immune tolerance to the fetus (2,3), and on recent observations that embryonic tissues exhibit reduced immunogenicity in various transplantation settings (4)(5)(6)(7). Considering that very early embryonic tissues are associated with a substantial risk of teratoma formation, we have attempted, during the past several years, to define the earliest gestational time point that does not pose a teratoma risk for transplantation of different embryonic pig tissues, including kidney (6), heart (unpublished), spleen (8), pancreas, liver, and lung (7) into SCID mice.…”

Hepatic reconstruction from fetal porcine liver cells using a radial flow bioreactor

“…Thus, the earliest time after organogenesis is established appears to be preferable for human transplantation. In fact, Friedman et al [13] have shown that maximal liver growth and function were achieved at the earliest teratoma-free gestational age of embryonic day (E) 28. In this study, the possibility of teratoma development was also taken into consideration, and construction of a BAL system was achieved with a RFB and fetal porcine livers obtained on E35 as the cell source, while E56 cells were also examined for comparison.…”