Investigation of the molecular basis of extraembryonic lineage specification in humans

• Project/Area Number: 18K09216
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Tohoku University
• Principal Investigator: Hiroaki Okae 東北大学, 医学系研究科, 准教授 (10582695)
• Co-Investigator(Kenkyū-buntansha): 有馬 隆博 東北大学, 医学系研究科, 教授 (80253532)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ヒト胎盤 / 胎盤トロフォブラスト幹（TS)細胞 / エピジェネティクス / ダイレクトリプログラミング / 胎盤トロフォブラスト幹（TS）細胞

Outline of Final Research Achievements

A mammalian zygote undergoes cleavage divisions to form a blastocyst that is composed of inner cell mass (ICM) and trophectoderm (TE). In mice, many transcription factors including CDX2 and EOMES have been identified as essential for the specification of the TE lineage. However, little is known about how the TE lineage is specified in human preimplantation embryos. This study aimed to identify factors involved in this process. To this end, we identified transcription factors specifically expressed in undifferentiated human TS cells. Although it turned out to be difficult to derive induced TS (iTS) cells from somatic cells with these transcription factors, we successfully converted human ES/iPS cells into iTS cells by overexpressing GATA2, GATA3, or TFAP2A. These transcription factors may be involved in the regulation of early lineage specification in humans.

Academic Significance and Societal Importance of the Research Achievements

ヒトiTS細胞の誘導に有効であったGATA2、GATA3、TFAP2Aは、マウスの胎盤発生においても重要な役割を担うことが報告されている。一方、CDX2やEOMESを用いてヒトiTS細胞を誘導することはできない。よって、TE系譜への運命決定機構は、ヒトとマウスの間で一部保存されていることが明らかとなった。ヒト着床前胚における細胞運命決定機構の理解は、不妊や流産の原因の解明や、安全な生殖補助医療の提供などに役立つと期待される。

Research Products

• [Int'l Joint Research] CBI Toulouse/Universite de Nantes(フランス)
• [Int'l Joint Research] McGill University/University of Western Ontario(カナダ)
• [Int'l Joint Research] University of Kansas Medical Center(米国)
• [Int'l Joint Research] CNRS(フランス)
• [Journal Article] ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development (2021)
  • Author(s): Varberg Kaela M.、Iqbal Khursheed、Muto Masanaga、Simon Mikaela E.、Scott Regan L.、Kozai Keisuke、Choudhury Ruhul H.、Aplin John D.、Biswell Rebecca、Gibson Margaret、Okae Hiroaki、Arima Takahiro、Vivian Jay L.、Grundberg Elin、Soares Michael J.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 10
  • DOI: 10.1073/pnas.2016517118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Naive Human Embryonic Stem Cells Can Give Rise to Cells with a Trophoblast-like Transcriptome and Methylome (2020)
  • Author(s): Cinkornpumin Jessica K.、Kwon Sin Young、Guo Yixin、Hossain Ishtiaque、Sirois Jacinthe、Russett Colleen S.、Tseng Hsin-Wei、Okae Hiroaki、Arima Takahiro、Duchaine Thomas F.、Liu Wanlu、Pastor William A.
  • Journal Title: Stem Cell Reports Volume: 15 Issue: 1 Pages: 198-213
  • DOI: 10.1016/j.stemcr.2020.06.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histone deacetylase 1 and 2 drive differentiation and fusion of progenitor cells in human placental trophoblasts (2020)
  • Author(s): Jaju Bhattad Gargi、Jeyarajah Mariyan J.、McGill Megan G.、Dumeaux Vanessa、Okae Hiroaki、Arima Takahiro、Lajoie Patrick、B?rub? Nathalie G.、Renaud Stephen J.
  • Journal Title: Cell Death & Disease Volume: 11 Issue: 5 Pages: 311-327
  • DOI: 10.1038/s41419-020-2500-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Atypical protein kinase C iota (PKCλ/ι) ensures mammalian development by establishing the maternal?fetal exchange interface (2020)
  • Author(s): Bhattacharya Bhaswati、Home Pratik、Ganguly Avishek、Ray Soma、Ghosh Ananya、Islam Md. Rashedul、French Valerie、Marsh Courtney、Gunewardena Sumedha、Okae Hiroaki、Arima Takahiro、Paul Soumen
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 117 Issue: 25 Pages: 14280-14291
  • DOI: 10.1073/pnas.1920201117
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Unique features and emerging in vitro models of human placental development. (2020)
  • Author(s): Shun Shibata, Eri H Kobayashi, Norio Kobayashi, Akira Oike, Hiroaki Okae, Takahiro Arima.
  • Journal Title: Reprod Med Biol . Volume: 12 Issue: 4 Pages: 301-313
  • DOI: 10.1002/rmb2.12347
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of Human Trophoblast Stem Cells from Somatic Cells and Pluripotent Stem Cells (2020)
  • Author(s): Castel G, Meistermann D, Bretin B, Firmin J, Blin J, Loubersac S, Bruneau A, Chevolleau S, Kilens S, Chariau C, Gaignerie A, Francheteau Q, Kagawa H, Charpentier E, Flippe L, Francois-Campion V, Haider S, Dietrich B, Knofler M, Arima T, Bourdon J, Rivron N, Masson D, Fournier T, Okae H, Freour T, David L
  • Journal Title: Cell Reports Volume: 33 Issue: 8 Pages: 108419-108419
  • DOI: 10.1016/j.celrep.2020.108419
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] G protein subunit β1 is an important mediator of the late stage of endochondral ossification (2020)
  • Author(s): Ruengsinpinya Lerdluck、Murakami Tomohiko、Nakamura Eriko、Takahata Yoshifumi、Hata Kenji、Nakaminami Yuri、Okae Hiroaki、Nishimura Riko
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 533 Issue: 1 Pages: 90-96
  • DOI: 10.1016/j.bbrc.2020.08.119
  • Peer Reviewed / Open Access
• [Journal Article] Association of four imprinting disorders and ART (2019)
  • Author(s): Hattori H, Hiura H, Kitamura A, Miyauchi N, Kobayashi N, Takahashi S, Okae H, Kyono K, Kagami M, Ogata T, Arima T.
  • Journal Title: Clin Epigenetics Volume: 11 Issue: 1 Pages: 21-21
  • DOI: 10.1186/s13148-019-0623-3
  • Peer Reviewed / Open Access
• [Journal Article] Loss of p57KIP2expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells (2019)
  • Author(s): Takahashi Sota、Okae Hiroaki、Kobayashi Norio、Kitamura Akane、Kumada Kanako、Yaegashi Nobuo、Arima Takahiro
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 52 Pages: 26606-26613
  • DOI: 10.1073/pnas.1916019116
  • Peer Reviewed / Open Access
• [Journal Article] Cutting Edge: G Protein Subunit b 1 Negatively Regulates NLRP3 Inflammasome Activation (2019)
  • Author(s): Tomohiko Murakami, Lerdluck Ruengsinpinya, Eriko Nakamura,Yoshifumi Takahata, Kenji Hata, Hiroaki Okae,Shun’ichiro Taniguchi, Masafumi Takahashi and Riko Nishimura
  • Journal Title: The Journal of Immunology Volume: 202 Issue: 7 Pages: 1942-1947
  • DOI: 10.4049/jimmunol.1801388
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association of four imprinting disorders and ART. (2019)
  • Author(s): Hattori H, Hiura H, Kitamura A, Miyauchi N, Kobayashi N, Takahashi S, Okae H, Kyono K, Kagami M, Ogata T, Arima T.
  • Journal Title: Clinical Epigenetics Volume: 11 Pages: 21-21
  • Peer Reviewed / Open Access
• [Journal Article] Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A (2018)
  • Author(s): Dodo Mina、Kitamura Hiroshi、Shima Hiroki、Saigusa Daisuke、Wati Sisca Meida、Ota Nao、Katsuoka Fumiki、Chiba Hatsune、Okae Hiroaki、Arima Takahiro、Igarashi Kazuhiko、Koseki Takeyoshi、Sekine Hiroki、Motohashi Hozumi
  • Journal Title: The Journal of Biochemistry Volume: 165 Issue: 4 Pages: 323
  • DOI: 10.1093/jb/mvy108
  • NAID: 40021893390
  • Peer Reviewed / Open Access
• [Journal Article] Derivation of Human Trophoblast Stem Cells. (2018)
  • Author(s): Okae H, Toh H, Sato T, Hiura H, Takahashi S, Shirane K, Kabayama Y, Suyama M, Sasaki H, Arima T.
  • Journal Title: Cell Stem Cell Volume: 22 Pages: 50-63
  • Peer Reviewed / Open Access
• [Presentation] ヒトES細胞からTS細胞への分化転換を阻害するエピジェネティックバリアの同定 (2021)
  • Author(s): 岡江寛明
  • Organizer: AMED研究開発交流会
  • Invited
• [Presentation] Modeling human placental development and disease with stem cells (2021)
  • Author(s): 岡江寛明
  • Organizer: 第9回 東北大学スマート・エイジング学際重点研究センター シンポジウム
  • Invited
• [Presentation] 分化全能性の消失に関わるインプリント遺伝子の同定 (2020)
  • Author(s): 岡江寛明、小林記緒、有馬隆博
  • Organizer: 日本繁殖生物学会第113回大会
  • Invited
• [Presentation] Epigenetic restriction of human pluripotency by silencing of the chromosome 19 miRNA cluster (2020)
  • Author(s): 岡江寛明
  • Organizer: 第43回日本分子生物学会年会
  • Invited
• [Presentation] 着床前胚に由来する幹細胞を用いた全能性の再構築 (2020)
  • Author(s): 岡江寛明
  • Organizer: 新学術領域研究「全能性プログラム」Webinar
  • Invited
• [Presentation] Identification of an epigenetic barrier between human embryonic and trophoblast stem cells (2020)
  • Author(s): 岡江寛明
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] ヒトES細胞からTS細胞への運命転換 (2020)
  • Author(s): 岡江寛明
  • Organizer: 新学術領域研究「配偶子インテグリティの構築」「全能性プログラム」合同公開シンポジウム2020
  • Invited
• [Presentation] なぜ絨毛癌は稀なのか？ヒト栄養膜幹細胞を用いた胎盤の腫瘍化抑制機構の解析 (2019)
  • Author(s): 岡江 寛明
  • Organizer: 第42回日本分子生物学会年会
  • Int'l Joint Research / Invited
• [Presentation] ヒト胚性幹細胞の栄養膜幹細胞への分化転換 (2019)
  • Author(s): 小林 記緒
  • Organizer: 第42回日本分子生物学会年会
  • Int'l Joint Research
• [Presentation] ヒト胎盤異常のエピゲノム～全胞状奇胎の細胞特性の解析～ (2019)
  • Author(s): 有馬 隆博
  • Organizer: 日本人類遺伝学会第64回大会
  • Int'l Joint Research / Invited
• [Presentation] ヒト胎盤幹（TS）細胞の樹立とその細胞特性 (2019)
  • Author(s): 小林記緒、樋浦仁、岡江寛明、有馬隆博
  • Organizer: 第14回日本生殖発生医学会学術集会
  • Invited
• [Presentation] Derivation of Human Trophoblast Stem Cells from Blastocysts and Villous Cytotrophoblast Cells. (2019)
  • Author(s): Okae H. ArimaT.
  • Organizer: International Symposium on Epigenome 2019
  • Int'l Joint Research / Invited
• [Presentation] ヒト胎盤のトロフォブラスト幹細胞の樹立と臨床への応用 (2018)
  • Author(s): 小林記緒、樋浦仁、岡江寛明、有馬隆博
  • Organizer: 第70回日本産科婦人科学会学術講演会
  • Invited
• [Presentation] ARTによるエピジェネティクスの変調 (2018)
  • Author(s): 小林記緒、樋浦仁、岡江寛明、有馬隆博
  • Organizer: 第63回日本生殖医学会学術講演会・総会
  • Invited
• [Presentation] Derivation of human trophoblast stem cells. (2018)
  • Author(s): Okae H. ArimaT.
  • Organizer: Cold Spring Harbor Asia meeting on Stem Cell Crossroads.
  • Int'l Joint Research / Invited
• [Book] 加齢によるエピジェネティクス変異 (2019)
  • Author(s): 服部裕充、小林記緒、岡江寛明、有馬隆博
  • Total Pages: 7
  • Publisher: 医学書院
• [Book] プラダー・ウィリ症候群 (2019)
  • Author(s): 岡江寛明, 有馬隆博.
  • Total Pages: 1
  • Publisher: 雑誌診断と治療社
• [Book] プラダー・ウィリ症候群. (2019)
  • Author(s): 岡江寛明, 有馬隆博.
  • Total Pages: 1
  • Publisher: 雑誌診断と治療社
• [Book] ヒト栄養膜幹細胞の樹立. (2018)
  • Author(s): 岡江寛明, 有馬隆博.
  • Total Pages: 4
  • Publisher: 羊土社
• [Book] Therapeutic approaches to imprinting diseases. Epigenetics in Human Disease, (2018)
  • Author(s): Hattori H, Hiura H, Kobayashi N, Takahashi S, Okae H, Arima T.
  • Total Pages: 6
  • Publisher: Academic Press.