Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have promising potential for opening new avenues in regenerative medicine. However, since the tumorigenic potential of undifferentiated pluripotent stem cells (PSCs) is a major safety concern for clinical transplantation, inducible Caspase-9 (iC9) is under consideration for use as a fail-safe system. Here, we used targeted gene editing to introduce the iC9 system into human iPSCs, and then interrogated the efficiency of inducible apoptosis with normal iPSCs as well as diseased iPSCs derived from patients with acute myeloid leukemia (AML-iPSCs). The iC9 system induced quick and efficient apoptosis to iPSCs in vitro. More importantly, complete eradication of malignant cells without AML recurrence was shown in disease mouse models by using AML-iPSCs. In parallel, it shed light on several limitations of the iC9 system usage. Our results suggest that careful use of the iC9 system will serve as an important countermeasure against posttransplantation adverse events in stem cell transplantation therapies.
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We thank Miki Ando and Motoo Watanabe (The University of Tokyo) for helpful discussions; Atsushi Miyawaki and Satoshi Iwano (RIKEN) for kindly providing AkaLuc gene and Akalumine-HCl (TokeOni); and Austin Smith and Yasuhiro Takashima (University of Cambridge) for kindly providing PiggyBac donor and transposase plasmids.
The project was supported in part by a grant from California Institute for Regenerative Medicine (CIRM; LA1_C12-06917, QUEST DISC2-08874), Weston Havens Foundation, and a research fellowship from Japan Society for the Promotion of Science (JSPS).
Conflict of interest
RM is a co-founder, equity holder, and serves on the Board of Directors of Forty Seven, Inc. HN is a co-founder, member of the scientific advisory board, and shareholder of Megakaryon Corp., iCELL, Inc. and Century Therapeutics, LLC. The remaining authors declare no conflict of interest.
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Nishimura, T., Xu, H., Iwasaki, M. et al. Sufficiency for inducible Caspase-9 safety switch in human pluripotent stem cells and disease cells. Gene Ther 27, 525–534 (2020). https://doi.org/10.1038/s41434-020-0179-z