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Generation of hypothalamic neural stem cells in vitro from human pluripotent stem cells

Research Project

Project/Area Number 20K08859
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionNagoya University

Principal Investigator

Suga Hidetaka  名古屋大学, 医学系研究科, 准教授 (20569818)

Co-Investigator(Kenkyū-buntansha) 有馬 寛  名古屋大学, 医学系研究科, 教授 (50422770)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Keywordsヒト多能性幹細胞 / 視床下部 / 幹細胞 / 神経幹細胞
Outline of Research at the Start

ヒト多能性幹細胞(ES細胞、iPS細胞)から視床下部神経幹細胞への分化誘導法を確立し、誘導した細胞が神経幹細胞として機能を果たすことを示す。
視床下部神経組織は再生能力が低く、一旦傷つくと回復は難しい。我々はマウスES細胞から視床下部神経を分化させ、その中に増殖能と分化能とを併せ持った細胞、すなわち神経幹細胞が存在することを証明し、単離することに成功した。一方、ヒトでは生体から視床下部組織を採取することが難しく、神経幹細胞の研究は進んでいない。本研究ではヒトES細胞・iPS細胞を利用し、vitroでの分化技術と合わせ、ヒトの視床下部における神経幹細胞の存在に迫る。

Outline of Final Research Achievements

In this study, we induced human hypothalamic neural tissue organoids using human ESCs (hESCs), attempted to fractionate hypothalamic neural stem cell-like cells from the organoids, and examined whether these fractionated cells have tissue stem cell properties.
We focused on RAX and differentiated RAX::VENUS knock-in hESCs into hypothalamic organoids and sorted RAX-positive cells from mature organoids. The isolated RAX-positive cells formed neurospheres and exhibited self-renewal and multipotency. Neurogenesis was observed when neurospheres were transplanted into the mouse hypothalamus. We isolated RAX-positive hypothalamic neural stem cell-like cells from wild-type human ES organoids. This is the first study to differentiate human hypothalamic neural stem cell-like cells from pluripotent stem cells.

Academic Significance and Societal Importance of the Research Achievements

ヒトES細胞から視床下部神経幹細胞の性質を持つ細胞を作製する基盤技術ができたと考えられる。視床下部は体の恒常性を保つ重要な器官だがひとたび傷つくと回復しない。今後視床下部障害を来した患者さんに対する再生医療実現のための技術となることが期待される。またマウスの視床下部神経幹細胞から分泌されるエクソソームは抗加齢作用を持つと報告されており、加齢に関する研究にも役立つと考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (44 results)

All 2023 2022 2021 2020

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 8 results) Presentation (33 results) (of which Int'l Joint Research: 5 results,  Invited: 16 results) Book (1 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Recipe for pituitary organoids.2023

    • Author(s)
      Kano M*, Sasaki H, Miwata T, Suga H*
    • Journal Title

      Frontiers in Endocrinology

      Volume: 13 Pages: 1025825-1025825

    • DOI

      10.3389/fendo.2022.1025825

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation of hypothalamic neural stem cell-like cells in vitro from human pluripotent stem cells.2023

    • Author(s)
      Miwata T, Suga H*, Kawaguchi Y, Sakakibara M, Kano M, Taga S, Soen M, Ozaki H, Asano T, Sasaki H, Miyata T, Yasuda Y, Kobayashi T, Sugiyama M, Onoue T, Takagi H, Hagiwara D, Iwama S, Arima H,
    • Journal Title

      Stem Cell Reports

      Volume: 18 Issue: 4 Pages: 869-883

    • DOI

      10.1016/j.stemcr.2023.02.006

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Differentiation of human induced pluripotent stem cells into hypothalamic vasopressin neurons with minimal exogenous signals and partial conversion to the naive state2022

    • Author(s)
      Ozaki Hajime、Suga Hidetaka、Sakakibara Mayu、Miyake Natsuki、Miwata Tsutomu、Taga Shiori、Nagai Takashi、Kano Mayuko、Mitsumoto Kazuki、Miyata Takashi、Kobayashi Tomoko、Sugiyama Mariko、Onoue Takeshi、Takagi Hiroshi、Hagiwara Daisuke、Iwama Shintaro、Banno Ryoichi、Iguchi Genzo、Takahashi Yutaka、Arima Hiroshi
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 17381-17381

    • DOI

      10.1038/s41598-022-22405-8

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional Lactotrophs in Induced Adenohypophysis Differentiated From Human iPS Cells2022

    • Author(s)
      Miyake Natsuki, Nagai Takashi, Suga Hidetaka, Inoshita Naoko, Arima Hiroshi, Kajiyama Hiroaki, et al
    • Journal Title

      ENDOCRINOLOGY

      Volume: 163(3) Issue: 3 Pages: 1-7

    • DOI

      10.1210/endocr/bqac004

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A new primate model of hypophyseal dysfunction.2021

    • Author(s)
      Kawabata T, Suga H, Takeuchi K, Nagata Y, Sakakibara M, Ushida K, Ozone C, Enomoto A, Kawamoto I, Itagaki I, Tsuchiya H, Arima H, Wakabayashi T.
    • Journal Title

      Scientific Reports

      Volume: 24 Issue: 1 Pages: 10729-10729

    • DOI

      10.1038/s41598-021-90209-3

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Induction of Functional Hypothalamus and Pituitary Tissues From Pluripotent Stem Cells for Regenerative Medicine2021

    • Author(s)
      Mayuko Kano, Hidetaka Suga, Hiroshi Arima
    • Journal Title

      Journal of the Endocrine Society

      Volume: 5 Issue: 3

    • DOI

      10.1210/jendso/bvaa188

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypothalamic-pituitary organoid generation through the recapitulation of organogenesis2021

    • Author(s)
      Hajime Ozaki, Hidetaka Suga, Hiroshi Arima
    • Journal Title

      Development, growth & differentiation

      Volume: 83 Issue: 2 Pages: 154-165

    • DOI

      10.1111/dgd.12719

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ndoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice2020

    • Author(s)
      Yohei Kawaguchi, Daisuke Hagiwara, Takashi Miyata, Yuichi Hodai, Junki Kurimoto, Hiroshi Takagi, Hidetaka Suga, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Yoshihiro Ito, Shintaro Iwama, Ryoichi Banno, Valery Grinevich, Hiroshi Arima
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 19730-19730

    • DOI

      10.1038/s41598-020-76839-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 視床下部・下垂体の再生医療とその先2023

    • Author(s)
      須賀英隆、有馬寛
    • Organizer
      第33回日本間脳下垂体腫瘍学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] ヒト多能性幹細胞から分化誘導した脳下垂体細胞の成熟方法2023

    • Author(s)
      須賀英隆、多賀詩織、中野徳重、桑原篤、松本隆作、加納麻弓子、三輪田勤、有馬寛
    • Organizer
      第22回日本再生医療学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Making hypothalamatic-pituitary organoids in a dish.2022

    • Author(s)
      Hidetaka Suga
    • Organizer
      Yogesh C. Patel Memorial Lecture, McGill University Endocrinology Research and Education Day
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ヒト視床下部神経幹細胞のin vitro分化創出2022

    • Author(s)
      三輪田勤
    • Organizer
      第95回日本内分泌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] DeepLearningによるヒトES細胞培養過程の予測2022

    • Author(s)
      淺野 友良 筒井 奎剛, 須賀 英隆, 新岡 宏彦, 湯川 博, 有馬 寛
    • Organizer
      第40回内分泌代謝学サマーセミナー
    • Related Report
      2022 Annual Research Report
  • [Presentation] ヒト多能性幹細胞からの機能的な視床下部-下垂体ユニット作製2022

    • Author(s)
      須賀 英隆、有馬 寛
    • Organizer
      生理学・生化学分科会/獣医繁殖学分科会合同シンポジウム、第165回日本獣医学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 下垂体の再生研究2022

    • Author(s)
      須賀英隆、松本隆作、有馬寛
    • Organizer
      第26回日本内分泌病理学会学術総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 視床下部・下垂体再生医療研究の最前線2022

    • Author(s)
      須賀英隆、松本隆作、高橋裕、有馬寛
    • Organizer
      第32回臨床代謝学Update
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 下垂体の再生2022

    • Author(s)
      須賀英隆、有馬寛
    • Organizer
      第32回日本間脳下垂体腫瘍学会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Regeneration of Parethyroid Glands that Function in Response to Calcium.2021

    • Author(s)
      Kano M., Mizuno N., Mizutani E., Suga H., Arima H.
    • Organizer
      JES-KES Joint Symposium, the 9th Seoul International Congress of Endocrinology and Metabolism in conjunction with the 40th Annual Scientific Meeting of Korean Endocrine Society (SICEM 2021)
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] カルシウム応答性を有する機能的な副甲状腺再生2021

    • Author(s)
      加納麻弓子、水野直彬、水谷英二、正木英樹、須賀英隆、中内啓光
    • Organizer
      第94回日本内分泌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] マウスES細胞を用いたキスペプチンニューロンを含む視床下部弓状核の分化誘導法の検討2021

    • Author(s)
      三宅菜月、須賀英隆、大須賀智子、井上直子、上野山賀久、小谷友美、梶山広明、束村博子、有馬寛
    • Organizer
      第94回日本内分泌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 家族性中枢性尿崩症(FNDI)ヒトiPS細胞からのバソプレシン(AVP)ニューロンの分化誘導2021

    • Author(s)
      尾崎創、三輪田勤、光本一樹、須賀英隆、有馬寛
    • Organizer
      第94回日本内分泌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 機械学習を用いた下垂体オルガノイド分化効率予測モデルの作成2021

    • Author(s)
      松本 隆作、須賀 英隆、青井 貴之、高橋 裕、山本 拓也
    • Organizer
      第94回日本内分泌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 試験管内で再現する視床下部‐下垂体オルガノイド2021

    • Author(s)
      須賀英隆、有馬寛
    • Organizer
      第94回日本内分泌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 視床下部・下垂体の再生医学2021

    • Author(s)
      笠井貴敏、須賀英隆、有馬寛
    • Organizer
      第110回日本病理学会「特別シンポジウム2 再生医療の最前線」
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] ヒトES細胞を用いてタニサイト様細胞への分化誘導を試みる2021

    • Author(s)
      三輪田勤、須賀英隆、尾崎創、有馬寛
    • Organizer
      第39回内分泌・代謝学サマーセミナー
    • Related Report
      2021 Research-status Report
  • [Presentation] ナイーブ化による家族性中枢性尿崩症(FNDI)ヒト疾患特異的iPS細胞からのバソプレシン(AVP)ニューロンの分化誘導2021

    • Author(s)
      尾崎創、須賀英隆、三輪田勤、有馬寛
    • Organizer
      第39回内分泌・代謝学サマーセミナー
    • Related Report
      2021 Research-status Report
  • [Presentation] ヒトiPS細胞を用いた下垂体発生・疾患研究2021

    • Author(s)
      松本隆作、須賀英隆、高橋裕、山本拓也
    • Organizer
      第39回内分泌・代謝学サマーセミナー
    • Related Report
      2021 Research-status Report
  • [Presentation] iPS 細胞を用いた革新的下垂体疾患モデルの作成と病因・病態解析2021

    • Author(s)
      高橋 裕、松本隆作、蟹江慶太郎、伊藤 剛、金子 新、 須賀英隆、福岡秀規、井口元三
    • Organizer
      第35回日本下垂体研究会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 視床下部-下垂体系の再生医療2021

    • Author(s)
      須賀英隆、有馬 寛
    • Organizer
      第35回日本下垂体研究会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 試験管内で作る視床下部・下垂体2021

    • Author(s)
      須賀英隆、有馬寛
    • Organizer
      第22回日本内分泌学会関東甲信越支部学術集会・総会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 多能性幹細胞を用いた神経内分泌器官作出と機能解析2021

    • Author(s)
      加納麻弓子、水野直彬、水谷英二、須賀英隆、有馬寛、中内啓光
    • Organizer
      第47回日本神経内分泌学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] ヒト疾患特異的人工多能性幹細胞(iPS細胞)からのバソプレシン(AVP)神経の分化誘導による家族性中枢性尿崩症(FNDI)のin vitroヒト疾患モデル2021

    • Author(s)
      尾崎創、須賀英隆、三輪田勤、井口元三、高橋裕、有馬寛
    • Organizer
      第47回日本神経内分泌学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 視床下部・下垂体の再生医療研究2021

    • Author(s)
      須賀英隆、有馬寛
    • Organizer
      Kidney & Endocrine Researchers Web Seminar
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] シャーレの上の視床下部-下垂体2021

    • Author(s)
      須賀英隆、有馬寛
    • Organizer
      第3回最先端循環代謝学の若手研究会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] Toward the regenerative medicine for hypothalamic and pituitary disorders using pluripotent stem cells2021

    • Author(s)
      Hidetaka Suga, Hiroshi Arima
    • Organizer
      The 19th International Congress of Endocrinology (ICE Virtual 2021)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Spatial transcriptomics for the analysis of human pituitary development2021

    • Author(s)
      Ryusaku Matsumoto, Mio Kabata, Hidetaka Suga, Takuya Yamamoto
    • Organizer
      Endocrine Society Annual Meeting 2021 (ENDO2021)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 視床下部-下垂体系の機能的連携2021

    • Author(s)
      須賀英隆、松本隆作、笠井貴敏、有馬寛
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ES/iPS細胞から視床下部‐下垂体組織の作製2021

    • Author(s)
      須賀英隆
    • Organizer
      第126回日本解剖学会総会・全国学術集会/第98回日本生理学会大会合同大会
    • Related Report
      2020 Research-status Report
  • [Presentation] Making a Pituitary Gland in a Dish2020

    • Author(s)
      Hidetaka Suga, Hiroshi Arima.
    • Organizer
      The 17th Asia-Oceania Congress of Endocrinology and the 8th Seoul International Congress of Endocrinology and Metabolism (AOCE-SICEM 2020)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 視床下部・下垂体のin vitro分化による研究2020

    • Author(s)
      須賀英隆、有馬寛
    • Organizer
      第93回日本内分泌学会
    • Related Report
      2020 Research-status Report
  • [Presentation] 視床下部・下垂体の再生医療2020

    • Author(s)
      須賀英隆、尾崎創、三輪田勤、三宅菜月、加納麻弓子、多賀詩織、桑原篤、木村徹、中野徳重、小林久美子、北本幸子、有馬寛
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Research-status Report
  • [Book] 視床下部-下垂体の再生医療(最先端ナノライフシステム研究編集委員会編「最先端ナノライフシステム研究」pp.160-168)2022

    • Author(s)
      須賀英隆
    • Total Pages
      221
    • Publisher
      丸善プラネット
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] 下垂体ホルモン産生細胞の移植2023

    • Inventor(s)
      須賀英隆、佐々木博勇、桑原篤、多賀詩織、中野徳重
    • Industrial Property Rights Holder
      東海国立大学機構
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2023-021207
    • Filing Date
      2023
    • Related Report
      2022 Annual Research Report
  • [Patent(Industrial Property Rights)] 細胞表面マーカーを用いた下垂体細胞および視床下部細胞の分離法2021

    • Inventor(s)
      小谷侑、河田美穂、長崎弘、須賀英隆
    • Industrial Property Rights Holder
      名古屋大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-158406
    • Filing Date
      2021
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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