News and Events
News and Events
March 08, 2023
A safer method of generating pancreatic islet-like cells from human iPS cells by inhibiting cyclin-dependent kinase CDK8/19
There are currently high expectations for the transplantation of pancreatic islet-like cells produced from human pluripotent stem cells like human iPS cells and ES cells to revolutionize diabetes treatment in the future. While it is possible to stringently evaluate and manage the risk posed by residual culture media components used during production by performing an impurity assessment on the final product, it is difficult to accurately assess the tumorigenic potential of the resulting islet-like cells in advance and conduct quality control.
In this study, the research group conducted a safety assessment of various differentiation inducers used to generate pancreatic islet-like cells from human iPS cells and found one reagent, ALK5 inhibitor II, to possess significant mutagenic potential.
During their attempts to replace the mutagenic ALK5 inhibitor II, they discovered that it has an inhibitory effect on cyclin-dependent kinase CDK8/19. The group further found that this CDK8/19 inhibition plays a crucial role in the differentiation process, leading them to establish a safer induction method to produce iPICs by switching to a combination of non-mutagenic CDK8/19 and ALK5 inhibitors.
These findings illuminate the underlying mechanisms involved in differentiating human pluripotent stem cells into islet-like cells and serve as an example of risk minimization against potentially harmful raw materials used in preparing cell therapy products.
The research results were published online in the British scientific journal Stem Cell Research & Therapy on January 5, 2023.
- Journal: Stem Cell Research & Therapy
- Title: CDK8/19 inhibition plays an important role in pancreatic β‑cell induction from human iPSCs
Kensuke Sakuma1,2*, Noriko Tsubooka‑Yamazoe1,2, Kiyohiro Hashimoto3, Nozomu Sakai4, Shinya Asano5, Saori Watanabe‑Matsumoto2,7, Takeshi Watanabe3, Bunnai Saito4, Hirokazu Matsumoto2,6, Hikaru Ueno1,2, Ryo Ito1,2 and Taro Toyoda2,7*
* Corresponding Author
- Author Affiliations:
- iPSC-Derived Pancreatic Islet Cell (iPIC) Therapy Department, Orizuru Therapeutics Inc., Fujisawa, Kanagawa, Japan
- Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan
- Drug Safety Research and Evaluation Group, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
- Drug Discovery Sciences, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
- Integrated & Translational Science, Axcelead Drug Discovery Partners, Inc., Fujisawa, Kanagawa, Japan
- T-CiRA Discovery and Innovation, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
- Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan