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Acknowledgements
We thank Drs. Shinya Yamanaka and Seigo Izumo for supporting this project. We also
thank Takako Sono, Ayaka Sakoda, Miyuki Nomura, Yuko Ishikawa, and Haruka
Yamamoto (T-CiRA) for preparing some of the materials and technical assistance, and
Azusa Hama and Yoko Uematsu (CiRA), Shizuka Murakami, Yoshimitsu Nakashima,
Reiko Oikawa (Takeda Pharmaceutical Company Limited), Takanori Matsuo and Aya
Higashide (T-CiRA) for their administrative support. We also thank Peter Karagiannis
(CiRA) for reading the manuscript. We used development samples provided free from
Oji Holdings Corporation for the analysis. This research was supported by the
Takeda–CiRA collaboration program, a grant from Takeda Pharmaceutical Company
Limited, a grant from the Leducq Foundation (18CVD05), a grant from SECOM Science
and Technology Foundation, grants from the Research Center Network for Realization of
Regenerative Medicine (JP19bm0104001, JP19bm0204003, JP19bm0804008, and
JP20bm0804022), Research on Regulatory Science of Pharmaceuticals and Medical
Devices (JP19mk0104117), and Research Project for Practical Applications of Regenerative Medicine (JP19bk0104095) provided by the Japan Agency for Medical Research
and Development, JSPS KAKENHI Grants (JP18K15120, JP18KK0461, JP19K16041 and
JP17H04176) and the iPS Cell Research Fund. Kyoto University and Takeda Pharmaceutical Company Limited have filed a patent application broadly relevant to this work.
Author contributions
K.M., K.D., M.N.-K., N.T., K.I., T.N., and Y.Y. conceived and designed the project. K.M.,
K.D., M.N.-K., S.K., Y.F., M.S., Y.N., I.T. and S.C.N. performed the experimental work.
T.S. and S.I. performed the CRISPR constructions. M.S., A.L.-C., C.O., M.N., T.M., and
T.A. analyzed the RNA-seq data. T.H. and Y.F. performed the transmission electron
microscopy work. K.M., K.D., M.N.-K., A.L.-C., T.N., and Y.Y. wrote the manuscript.
All authors discussed the results.
Competing interests
Y.Y. received research expense from Takeda Pharmaceutical Company, Ltd, and K.D.,
S.K., S.C.N., S.I, T.M., T.A., N.T., K.I., T.N. are employees of Takeda Pharmaceutical
Company, Ltd. K.M., S.K., and Y.Y. are the inventors of the patent application
(WO2019/189554). The other authors declare no competing interests.
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Supplementary information The online version contains supplementary material
available at https://doi.org/10.1038/s41467-021-23816-3.
Correspondence and requests for materials should be addressed to T.N. or Y.Y.
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