@article{e6ac901b1b324c47b3cc69893445136c,
title = "Human PSCs determine the competency of cerebral organoid differentiation via FGF signaling and epigenetic mechanisms",
abstract = "Various culture methods have been developed for maintaining human pluripotent stem cells (PSCs). These PSC maintenance methods exhibit biased differentiation; for example, feeder-dependent PSCs efficiently yield cerebral organoids, but it is difficult to generate organoids from feeder-free PSCs. It remains unknown how PSC maintenance conditions affect differentiation. In this study, we identified fibroblast growth factor (FGF) signaling in feeder-free PSC maintenance as a key factor that determines the differentiation toward cerebral organoids. The inhibition of FGF signaling in feeder-free PSCs rescued organoid generation to the same level in feeder-dependent cultures. FGF inhibition induced DNA methylation at the WNT5A locus, and this epigenetic change suppressed the future activation of non-canonical Wnt signaling after differentiation, leading to reliable cerebral organoid generation. This study underscores the importance of PSC culture conditions for directed differentiation into cerebral organoids, and the epigenetic status regulated by FGF signaling is involved in the underlying mechanisms.",
keywords = "Cell biology, Genomics, Omics, Stem cells research, Transcriptomics",
author = "Hirosato Ideno and Kent Imaizumi and Hiroko Shimada and Tsukasa Sanosaka and Akisa Nemoto and Jun Kohyama and Hideyuki Okano",
note = "Funding Information: We are grateful to N. Nakatsuji and H. Suemori (Kyoto University) for ESCs; S. Yamanaka and M. Nakagawa (Kyoto University) for iPSCs; M. Ishikawa (Keio University) for scientific advice, and all members of the H.O. laboratory for encouragement and kind support. This work was supported by funding from Japan Agency for Medical Research and Development (AMED) (Grant Number 19bm0804003, 20bm0804003, and 21bm0804003) to H.O.; Grant-in-Aid for Scientific Research on Innovative Areas “Singularity Biology (No. 8007)” (Grant Number 21H00438), Japan Society for the Promotion of Science (JSPS) (Grant Number 19K16927), Japan Science Society (Sasakawa Scientific Research Grant), the General Insurance Association of Japan, Takeda Science Foundation, Ikeda Scientific (Ikeda Rika Grant), Rikaken Holdings, Keio University Global Research Institute to K.I.; Keio University Research Grants for Life Science and Medicine to K.I. and H.I. Conceptualization, H.I. K.I. H.S. and H.O.; methodology, H.I. T.S. and K.I.; investigation, H.I. and K.I.; resources, T.S. A.N. and J.K.; data curation, H.I. T.S. and K.I.; writing – original draft, H.I. and K.I.; writing – review & editing, H.S. T.S. A.N. J.K. and H.O.; supervision, K.I. and H.O.; project administration, K.I. and H.O.; funding acquisition, H.I. K.I. and H.O. All authors read and approved the final manuscript. H.O. is a compensated scientific consultant for SanBio Co. Ltd. and K Pharma Inc. These companies have no relationship with the present study. The other authors declare no competing interest. Funding Information: We are grateful to N. Nakatsuji and H. Suemori (Kyoto University) for ESCs; S. Yamanaka and M. Nakagawa (Kyoto University) for iPSCs; M. Ishikawa (Keio University) for scientific advice, and all members of the H.O. laboratory for encouragement and kind support. This work was supported by funding from Japan Agency for Medical Research and Development (AMED) (Grant Number 19bm0804003 , 20bm0804003 , and 21bm0804003 ) to H.O.; Grant-in-Aid for Scientific Research on Innovative Areas “Singularity Biology (No. 8007)” (Grant Number 21H00438), Japan Society for the Promotion of Science (JSPS) (Grant Number 19K16927 ), Japan Science Society (Sasakawa Scientific Research Grant), the General Insurance Association of Japan , Takeda Science Foundation , Ikeda Scientific (Ikeda Rika Grant), Rikaken Holdings, Keio University Global Research Institute to K.I.; Keio University Research Grants for Life Science and Medicine to K.I. and H.I. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = oct,
day = "21",
doi = "10.1016/j.isci.2022.105140",
language = "English",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "10",
}