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Innovative disease modeling of pregnancy complications using human trophoblast stem cells

Research Project

Project/Area Number 21H03072
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionKumamoto University (2022-2023)
Tohoku University (2021)

Principal Investigator

Okae Hiroaki  熊本大学, 発生医学研究所, 教授 (10582695)

Co-Investigator(Kenkyū-buntansha) 柴田 峻  東北大学, 医学系研究科, 助教 (40885670)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2023: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2021: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywords胎盤 / 妊娠高血圧症候群 / 栄養膜幹細胞(TS細胞) / CRISPR / 栄養膜幹細胞 / ヒト胎盤 / 妊娠高血圧腎症 / 幹細胞 / 妊娠合併症
Outline of Research at the Start

胎盤は胎児と母体をつなぐ重要な臓器であり、その異常はさまざまな妊娠合併症の原因となる。応募者らは最近、妊娠初期のヒト胎盤から栄養膜幹細胞(TS細胞)を樹立することに成功した。本研究では、まずリプログラミングの手法を用い、妊娠中期以降の胎盤からTS細胞を高効率に誘導する技術を確立する。次に、この技術を活用し、代表的な妊娠合併症である妊娠高血圧腎症より疾患TS細胞を樹立する。さらに、試験管内で病態を再現するため、オルガノイド作製技術の開発にも取り組む。本研究で得られる成果は、これまであまり研究が進んでこなかった妊娠合併症の発症機構の解明や治療法の開発へと繋がると期待される。

Outline of Final Research Achievements

This study aims to investigate the pathogenesis of preeclampsia (PE) using human trophoblast stem cells (TSCs). We previously established TSCs from first-trimester human placentas, but it has not been able to apply the same technique to placentas obtained from later developmental stages. In this study, we established a method to establish TSCs from placentas in late gestation by transiently overexpressing SALL4 and a p53 dominant mutant. Next, we established human TSCs from early-onset PE patients and succeeded in recapitulating some key features of PE, such as abnormal secretion of angiogenic factors and abnormal invasion of extravillous cytotrophoblast cells.

Academic Significance and Societal Importance of the Research Achievements

多くの妊娠合併症は妊娠中期以降に発症するが、これまで妊娠中期以降の胎盤細胞を長期培養することはできなかった。本研究で確立したTS細胞の樹立法は、妊娠中期以降の胎盤にも適用することができるため、疾患の発症機構の解析や、医薬品のスクリーニングへの応用が期待される。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • Research Products

    (27 results)

All 2024 2023 2022 2021

All Journal Article (11 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 11 results,  Open Access: 11 results) Presentation (12 results) (of which Int'l Joint Research: 4 results,  Invited: 10 results) Book (4 results)

  • [Journal Article] Trophoblast stem cell-based organoid models of the human placental barrier2024

    • Author(s)
      Hori Takeshi、Okae Hiroaki、Shibata Shun、Kobayashi Norio、Kobayashi Eri H.、Oike Akira、Sekiya Asato、Arima Takahiro、Kaji Hirokazu
    • Journal Title

      Nature Communications

      Volume: 15 Issue: 1 Pages: 1-1

    • DOI

      10.1038/s41467-024-45279-y

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Modeling embryo-endometrial interface recapitulating human embryo implantation2024

    • Author(s)
      Shibata Shun、Endo Shun、Nagai Luis A. E.、H. Kobayashi Eri、Oike Akira、Kobayashi Norio、Kitamura Akane、Hori Takeshi、Nashimoto Yuji、Nakato Ryuichiro、Hamada Hirotaka、Kaji Hirokazu、Kikutake Chie、Suyama Mikita、Saito Masatoshi、Yaegashi Nobuo、Okae Hiroaki、Arima Takahiro
    • Journal Title

      Science Advances

      Volume: 10 Issue: 8

    • DOI

      10.1126/sciadv.adi4819

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Regulation of human trophoblast gene expression by endogenous retroviruses2023

    • Author(s)
      Frost Jennifer M.、Amante Samuele M.、Okae Hiroaki、Jones Eleri M.、Ashley Brogan、Lewis Rohan M.、Cleal Jane K.、Caley Matthew P.、Arima Takahiro、Maffucci Tania、Branco Miguel R.
    • Journal Title

      Nature Structural & Molecular Biology

      Volume: - Issue: 4 Pages: 527-538

    • DOI

      10.1038/s41594-023-00960-6

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape2023

    • Author(s)
      Varberg Kaela M.、Dominguez Esteban M.、Koseva Boryana、Varberg Joseph M.、McNally Ross P.、Moreno-Irusta Ayelen、Wesley Emily R.、Iqbal Khursheed、Cheung Warren A.、Schwendinger-Schreck Carl、Smail Craig、Okae Hiroaki、Arima Takahiro、Lydic Michael、Holoch Kristin、Marsh Courtney、Soares Michael J.、Grundberg Elin
    • Journal Title

      Nature Communications

      Volume: 14 Issue: 1 Pages: 4826-4826

    • DOI

      10.1038/s41467-023-40424-5

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CRISPR screening in human trophoblast stem cells reveals both shared and distinct aspects of human and mouse placental development2023

    • Author(s)
      Takanori Shimizu*, Akira Oike*, Eri H. Kobayashi*, Asato Sekiya, Norio Kobayashi, Shun Shibata, Hirotaka Hamada, Masatoshi Saito, Nobuo Yaegashi, Mikita Suyama, Takahiro Arima, and Hiroaki Okae. *T.S., A.O., and E.H.K. contributed equally to this work.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 120 Issue: 51

    • DOI

      10.1073/pnas.2311372120

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] CITED2 is a conserved regulator of the uterine-placental interface.2023

    • Author(s)
      Kuna Marija、Dhakal Pramod、Iqbal Khursheed、Dominguez Esteban M.、Kent Lindsey N.、Muto Masanaga、Moreno-Irusta Ayelen、Kozai Keisuke、Varberg Kaela M.、Okae Hiroaki、Arima Takahiro、Sucov Henry M.、Soares Michael J.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 120 Issue: 3 Pages: 120-123

    • DOI

      10.1073/pnas.2213622120

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genomic imprinting in human placentation2022

    • Author(s)
      Kobayashi Eri H.、Shibata Shun、Oike Akira、Kobayashi Norio、Hamada Hirotaka、Okae Hiroaki、Arima Takahiro
    • Journal Title

      Reproductive Medicine and Biology

      Volume: 21 Issue: 1

    • DOI

      10.1002/rmb2.12490

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The multifaceted role of GCM1 during trophoblast differentiation in the human placenta2022

    • Author(s)
      Jeyarajah Mariyan J.、Jaju Bhattad Gargi、Kelly Rachel D.、Baines Kelly J.、Jaremek Adam、Yang Fei-Hung P.、Okae Hiroaki、Arima Takahiro、Dumeaux Vanessa、Renaud Stephen J.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 119 Issue: 49

    • DOI

      10.1073/pnas.2203071119

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The microRNA cluster C19MC confers differentiation potential into trophoblast lineages upon human pluripotent stem cells2022

    • Author(s)
      Kobayashi Norio、Okae Hiroaki、Hiura Hitoshi、Kubota Naoto、Kobayashi Eri H.、Shibata Shun、Oike Akira、Hori Takeshi、Kikutake Chie、Hamada Hirotaka、Kaji Hirokazu、Suyama Mikita、Bortolin-Cavaill? Marie-Line、Cavaill? J?r?me、Arima Takahiro
    • Journal Title

      Nature Communications

      Volume: 13 Issue: 1 Pages: 3071-3071

    • DOI

      10.1038/s41467-022-30775-w

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intersection of regulatory pathways controlling hemostasis and hemochorial placentation2021

    • Author(s)
      Muto Masanaga、Chakraborty Damayanti、Varberg Kaela M.、Moreno-Irusta Ayelen、Iqbal Khursheed、Scott Regan L.、McNally Ross P.、Choudhury Ruhul H.、Aplin John D.、Okae Hiroaki、Arima Takahiro、Matsumoto Shoma、Ema Masatsugu、Mast Alan E.、Grundberg Elin、Soares Michael J.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 50

    • DOI

      10.1073/pnas.2111267118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ASCL2 reciprocally controls key trophoblast lineage decisions during hemochorial placenta development2021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ヒト栄養膜幹細胞を用いた胎盤研究2024

    • Author(s)
      岡江寛明
    • Organizer
      第4回 有性生殖学会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 遺伝子機能にもとづくヒトとマウス胎盤の進化的対応関係の理解2023

    • Author(s)
      岡江寛明
    • Organizer
      第41回日本受精着床学会総会・学術講演会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Disease modeling with human trophoblast stem cells2023

    • Author(s)
      岡江寛明
    • Organizer
      The 18th International Symposium of the Institute Network for Biomedical Sciences
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 遺伝子からひも解くヒトとマウス胎盤の対応関係2023

    • Author(s)
      岡江寛明
    • Organizer
      第68回日本生殖医学会学術講演会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] ヒトとマウス胎盤の対応関係の理解2023

    • Author(s)
      岡江寛明
    • Organizer
      新学術・全能性 第5回公開シンポジウム
    • Related Report
      2023 Annual Research Report
  • [Presentation] Unlocking the mysteries of pregnancy with stem cells2023

    • Author(s)
      岡江寛明
    • Organizer
      熊本大学発生医学研究所セミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] The microRNA cluster C19MC confers differentiation potential into trophoblast lineages upon human PSCs2023

    • Author(s)
      岡江寛明
    • Organizer
      IRCMS seminar "New Horizons in Developmental Biology"
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] C19MC confers differentiation potential into trophoblast lineages upon human PSCs2023

    • Author(s)
      岡江寛明
    • Organizer
      熊本大学発生医学研究所セミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] C19MC is essential for the differentiation potential of hPSCs into trophoblast lineages2022

    • Author(s)
      岡江寛明
    • Organizer
      The 55th annual meeting of the Japanese Society of Developmental Biologists
    • Related Report
      2022 Annual Research Report
  • [Presentation] Critical role of genomic imprinting in human placental development2022

    • Author(s)
      岡江寛明
    • Organizer
      新学術・全能性 The International Symposium “Totipotency and Germ Cell Development”
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ヒト胚着床モデル-母胎アセンブロイド-の開発2021

    • Author(s)
      柴田峻、岡江寛明、有馬隆博
    • Organizer
      ART FORUM’21 生殖の分子機構への新たなアプローチ
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 生殖医学研究の最前線 進歩し続ける基礎研究2021

    • Author(s)
      岡江寛明、有馬隆博.
    • Organizer
      66th生殖医学会学術講演会・総会:シンポジウム
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] ヒト胎盤発生と幹細胞2021

    • Author(s)
      柴田峻、岡江寛明、有馬隆博
    • Total Pages
      5
    • Publisher
      医学書院(金原出版)
    • Related Report
      2021 Annual Research Report
  • [Book] ヒト初期発生におけるエピジェネティクス2021

    • Author(s)
      岡江寛明、有馬隆博
    • Total Pages
      6
    • Publisher
      羊土社
    • Related Report
      2021 Annual Research Report
  • [Book] トロホブラスト幹細胞と展開2021

    • Author(s)
      小林枝里、岡江寛明、有馬隆博
    • Total Pages
      6
    • Publisher
      メディカルレビュー社
    • Related Report
      2021 Annual Research Report
  • [Book] ヒトTS細胞を用いた胎盤疾患モデルの構築2021

    • Author(s)
      大池 輝, 小林 枝里, 小林 記緒, 柴田 峻, 岡江 寛明, 北村 茜, 宮内 尚子, 有馬 隆博
    • Total Pages
      5
    • Publisher
      北隆館/ニューサイエンス社
    • Related Report
      2021 Annual Research Report

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Published: 2021-04-28   Modified: 2025-01-30  

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