Establishment of a physiologically-relevant liver model for disease screening
| Project/Area Number |
20K22491
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0403:Biomedical engineering and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Danoy Mathieu 東京大学, 大学院工学系研究科(工学部), 助教 (90882621)
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| Project Period (FY) |
2020-09-11 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | hiPSCs / HSCs / Liver / Disease / LSECs / Hepatocytes / Inflammation / Immune / Coculture |
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| Outline of Research at the Start |
非アルコール性脂肪肝疾患(NAFLD)に代表される肝疾患が今や世界的な課題とな る中、創薬における肝細胞培養系の疾患モデルとしての重要性は益々高まっている。 しかし、様々な実質・非実質細胞が複雑な階層構造を形成し、特異的に相互作用す ることによってもたらされる肝臓の生理的機能や応答を再現することは非常に困難 である。本研究では、ヒトiPS細胞やキメラマウスなどから得られる高度なヒト肝臓 細胞を用い、生物工学的なアプローチを駆使することで、健常および疾患状態を再 現可能なヒト肝臓の生理的な新規階層的共培養モデルを提案する。
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| Outline of Final Research Achievements |
Ethical issues and species specificity have motivated the development of in vitro models of the liver for drug screening applications. Modeling of the liver is especially challenging due to its complexity, being composed of hierarchically organized hepatocytes, LSECs, and HSCs. Here, the focus was set on the development of the latter which are known to be involved in inflammatory regulation but spontaneously activate when cultured in vitro, causing issues in the modeling of physiology. To solve the issue, optimization of the microenvironment of HSCs in term of stiffness and composition was done via different ECM. By doing so, optimized conditions in which quiescence could be preserved were found and controlled activation, via inflammatory cytokines was also confirmed. Protocols for the differentiation of those cells were also optimized in terms of reproducibility. Coculture of the previously cited cell types was also performed in microfluidic biochips and are currently further studied.
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| Academic Significance and Societal Importance of the Research Achievements |
Physiologically-relevant models are highly sought for in notably drug screening applications but spontaneous activation of HSCs in vitro forces models towards pathological situation. In this work, we have focused on optimizing the culture of HSCs to regulate inflammatory reactions within the model.
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Report
(3 results)
Research Products
(4 results)
