Embryonic stem cell-derived endothelial progenitor cells reduce recurrent miscarriage in a mouse miscarriage model

[Speaker] Atsushi Daimon:1
[Co-author] Kiichiro Tomoda:1, Yoshifumi Morihara:1, Michio Asahi:1
1:Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Japan

Our group previously reported that bone marrow-derived endothelial progenitor cell (EPC) transfusion was able to reduce recurrent miscarriage in a mouse miscarriage model, crossing CBA/J female with DBA male mice. However, collected enough amounts of EPCs for transplantation from a donor may be one obstacle to realize this cell transplantation therapy in the future. In this study, we tried to propagate the sufficient amounts of EPC-like cells from embryonic stem cells (ES cells) that can grow indefinitely.
Considering the adverse effect of the immune response, it is necessary to use EPC-like cells differentiated from ES cells established from the same mouse strain as the mother. However, there are no CBA / J-derived ES cell lines reported yet, so we first tried to derive ES cells from blastocysts collecting from pregnant CBA/J mice. By employing a culture medium supplemented with leukemia inhibitory factor and two kinase chemical inhibitors, we were able to establish 10 CBA/J derived ES cell lines. Analysis of the established ES cell lines (self-proliferative ability test, stem cell marker confirmation test, pluripotency confirmation test and karyotype analysis test) confirmed their proliferation and differentiation abilities. Second, we attempted to differentiate the ES cell lines into EPC - like cells with a xeno-free method and could easily propagate enough quantities of the EPC-like cells for transplantations. Finally, the differentiated EPC - like cells were administered to the mouse miscarriage model via intravenous injection and abortion rates were examined. We found that administering the EPC-like cells reduced the miscarriage rate from 26.9% to 7%, suggesting that this method is effective as the bone marrow-derived EPC transplantation. Therefore, our results demonstrate proof of principle that pluripotent stem cell-derived EPC-like cell transfusion can be a therapeutic intervention for recurrent miscarriage in the future. We will examine further the mechanism of miscarriage prevention effect and effects of human pluripotent stem cell-derived EPC transplantation and will discuss our results in this meeting.

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