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Modeling pathogenesis of ADHD using cortical organoids differentiated from patient-derived iPS cells.

Research Project

Project/Area Number 19H03584
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionKobe University

Principal Investigator

Ichiro Sora  神戸大学, 医学研究科, 特命教授 (40322713)

Co-Investigator(Kenkyū-buntansha) 江口 典臣  神戸大学, 医学部附属病院, 助教 (80814566)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
KeywordsAD/HD / iPS細胞 / 幹細胞 / 大脳皮質 / ドーパミン / 脳神経疾患 / 発生・分化 / 中脳
Outline of Research at the Start

健常者およびAD/HD患者の細胞から作成したiPS細胞を、SFEBq法を用いて大脳皮質様構造を持つ神経組織へ分化誘導させる。分化させた大脳皮質の構造を免疫染色により解析により、AD/HD患者の神経発生の異常について検討する。また、iPS細胞をPA6細胞上で培養するSDIA法を用い、iPS細胞をドーパミン神経細胞へと分化させ、ドーパミン放出能力、ドーパミンの取り込みを解析する。更にメチルフェニデート等のAD/HD治療薬への反応性についても検討する。

Outline of Final Research Achievements

Pathogenesis of Attention-Deficit/Hyperactivity Disorder (AD/HD) is still unclear. We focused on telencephalon organoids derived from AD/HD patients to establish biological model of AD/HD. We generated induced pluripotent stem cells (iPS cells) derived from an AD/HD patient and differentiated them into telencephalon organoids.
Morphological analysis of the telencephalon organoids revealed the significant differences in the thickness of early cortex-like layer structures and the number of neurons between AD/HD and control. Further analysis showed the significant differences in the number of cell division and apoptosis, and proportion of proliferation and differentiation, that might lead the morphological alteration in the layer structures. These findings have been published in the paper (Zhang, Eguchi, Sora et al., Telencephalon Organoids Derived from an Individual with ADHD Show Altered Neurodevelopment of Early Cortical Layer Structure. Stem Cell Rev Rep. 2023. PMID: 36872412)

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、AD/HD者では大脳皮質の発生に変化が生じていることを示唆するものである。MRI等を用いた画像研究など、先行研究においてもAD/HDにおける大脳皮質の形態的変化が指摘されており、本研究成果の妥当性を支持していると考える。本研究で得られた大脳皮質オルガノイドはAD/HDにおける大脳皮質の発生を実験的に再現しており、AD/HDの生物モデルとして更なる研究に利用可能であると考えられる。本研究の成果はAD/HDの病態解明、新たな治療法の開発に利用可能であり、将来のAD/HD治療を促進するという社会的、学術的意義を有するものである。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (2 results)

All 2023 2021

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results)

  • [Journal Article] Telencephalon Organoids Derived from an Individual with ADHD Show Altered Neurodevelopment of Early Cortical Layer Structure2023

    • Author(s)
      Zhang Danmeng、Eguchi Noriomi、Okazaki Satoshi、Sora Ichiro、Hishimoto Akitoyo
    • Journal Title

      Stem Cell Reviews and Reports

      Volume: - Issue: 5 Pages: 1482-1491

    • DOI

      10.1007/s12015-023-10519-z

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Telencephalon organoid derived from iPSCs showed immature differentiation of cortical neurons of an ADHD individual.2021

    • Author(s)
      Danmeng Zhang, Noriomi Eguchi, Satoshi Okazaki, Ichiro Sora
    • Organizer
      第43回日本生物学的精神医学会
    • Related Report
      2020 Annual Research Report

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Published: 2019-04-18   Modified: 2024-01-30  

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