【Plenary Lecture 1】 Exploiting the organ niche for interspecies organogenesis PL-1
○ Hiromitsu Nakauchi Stanford University and The University of Tokyo
We postulated that an “organ niche” exists in a developing animal and that this niche was empty when development of an organ is genetically disabled. This organ niche should be compensated developmentally by blastocyst complementation using wild-type pluripotent stem cells（PSCs）. We showed that in Pdx-1 deficient mice, inter-species blastocyst complementation with rat PSCs can create functional rat pancreata（Kobayashi et al. Cell. 2010）. Although the resulting pancreata, made of rat PSC-derived cells, were functional they were of mouse size, making them insufficient for isolating the number of islets needed to treat diabetes in a rat model. We performed the reverse experiment, injecting mouse PSCs into Pdx-1 deficient rat blastocysts. The generated pancreata were composed of mouse PSCderived cells but were of rat size. Islets prepared from
these pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully maintained normal host blood glucose levels for over 370 days without immunosuppression （Yamaguchi and Sato et al. Nature 2017）. These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by interspecies organogenesis. To generate human organs, we need to have chimeraforming PSCs. However, human ES/iPS cells are epiblast stem cells（EpiSCs）and cannot contribute to chimera when injected into blastocysts. We recently showed that if cell survival is transiently promoted by expressing BCL2, EpiSCs and even lineage-committed progenitor cells can contribute to chimera formation （Masaki et al. Cell Stem Cell. 2016）. This system may provide a method for“targeted organ generation”.
【Plenary Lecture 2】 Evaluation of the transplantation of iPS cell-derived regenerated cardiomyocytes into mouse, rat, monkey and pig heart PL-2
○ Keiichi Fukuda, Kazuaki Nakajima, Shugo Tohyama, Tomohisa Seki, Fumiyuki Hattori, Shinsuke Yuasa, Jun Fujita Department of Cardiology, Keio University School of Medicine
No effective therapy was established except heart transplantation for the treatment of severe congestive heart failure. iPS cells is expected to be used as a tool for the treatment of severe congestive heart failure, because they have no immune-rejection and no ethical problems. We had established a method to generate iPS cells using Sendai virus and peripheral circulating T lymphocytes within a month, which do not destroy the genome. We also screened factors that was expressed at the future heart forming area, and identified several factors which play important roles in cardiac differentiation. Using these information, we could efficiently induce cardiomyocytes from mouse, common marmoset, and human ES and iPS cells. We performed transcriptome and metabolome analysis of the cardiomyocytes and ES/iPS cells, and found that there is a big difference of the metabolic pathways between them. We used this difference to purify
the cardiomyocytes and eliminated the residual iPS cells. In order to translate these results into clinics, we need an animal transplantation models. Thus, we transplanted human iPS cell-derived cardiomyocytes into immuno-deficient mice/rat, common marmoset and pig heart. Human iPS-derived cardiomyocytes could survive in the heart of the NOG mice and NPD-XSCID rat without immuno-depressant reagent, and formed an orderly tissue. They also survived in the marmoset heart for at least 3 months with immune-depressant reagent. In contrast, they were observed at 1 month after transplantation, but could not be observed after 2 months in the micro-mini pig although maximum dose of immune-depressant reagents were administered. In conclusion, appropriate animal model is required for the precise evaluation of result of transplantation human cells into animal.
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