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タイトル: CDK8/19 inhibition plays an important role in pancreatic β-cell induction from human iPSCs
著者: Sakuma, Kensuke
Tsubooka-Yamazoe, Noriko
Hashimoto, Kiyohiro
Sakai, Nozomu
Asano, Shinya
Watanabe-Matsumoto, Saori
Watanabe, Takeshi
Saito, Bunnai
Matsumoto, Hirokazu
Ueno, Hikaru
Ito, Ryo
Toyoda, Taro  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0002-2948-0525 (unconfirmed)
著者名の別形: 佐久間, 健介
山添, 則子
橋本, 清弘
坂井, 望
浅野, 真也
松本, さおり
渡辺, 武志
齊藤, 文内
松本, 寛和
上野, 光
伊藤, 亮
豊田, 太郎
キーワード: Human-induced pluripotent stem cells
Mutagenicity
Pancreatic islet cell
Activin receptor-like kinase 5 inhibitor II
CDK8/19 inhibitors
発行日: 5-Jan-2023
出版者: Springer Nature
BMC
誌名: Stem Cell Research & Therapy
巻: 14
論文番号: 1
抄録: [Background] Transplantation of differentiated cells from human-induced pluripotent stem cells (hiPSCs) holds great promise for clinical treatments. Eliminating the risk factor of malignant cell transformation is essential for ensuring the safety of such cells. This study was aimed at assessing and mitigating mutagenicity that may arise during the cell culture process in the protocol of pancreatic islet cell (iPIC) differentiation from hiPSCs. [Methods] We evaluated the mutagenicity of differentiation factors used for hiPSC-derived pancreatic islet-like cells (iPICs). We employed Ames mutagenicity assay, flow cytometry analysis, immunostaining, time-resolved fluorescence resonance energy transfer-based (TR-FRET) cell-free dose–response assays, single-cell RNA-sequencing and in vivo efficacy study. [Results] We observed a mutagenic effect of activin receptor-like kinase 5 inhibitor II (ALK5iII). ALK5iII is a widely used β-cell inducer but no other tested ALK5 inhibitors induced β-cells. We obtained kinase inhibition profiles and found that only ALK5iII inhibited cyclin-dependent kinases 8 and 19 (CDK8/19) among all ALK5 inhibitors tested. Consistently, CDK8/19 inhibitors efficiently induced β-cells in the absence of ALK5iII. A combination treatment with non-mutagenic ALK5 inhibitor SB431542 and CDK8/19 inhibitor senexin B afforded generation of iPICs with in vitro cellular composition and in vivo efficacy comparable to those observed with ALK5iII. [Conclusion] Our findings suggest a new risk mitigation approach for cell therapy and advance our understanding of the β-cell differentiation mechanism.
記述: サイクリン依存性キナーゼCDK8/19阻害はヒトiPS細胞からの膵島様細胞への分化誘導において重要な役割を果たす. 京都大学プレスリリース. 2023-02-27.
A safer method of generating pancreatic islet-like cells from human iPS cells by inhibiting cyclin-dependent kinase CDK8/19. 京都大学プレスリリース. 2023-03-08.
著作権等: © The Author(s) 2022
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
URI: http://hdl.handle.net/2433/279510
DOI(出版社版): 10.1186/s13287-022-03220-4
PubMed ID: 36600289
関連リンク: https://www.cira.kyoto-u.ac.jp/j/pressrelease/news/230227-110000.html
https://www.cira.kyoto-u.ac.jp/e/pressrelease/news/230308-110000.html
出現コレクション:学術雑誌掲載論文等

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