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Tissue Eng Part C Methods. 2018 Oct;24(10):605-615. doi: 10.1089/ten.TEC.2018.0228.

Induced Pluripotent Stem Cell Elimination in a Cell Sheet by Methionine-Free and 42°C Condition for Tumor Prevention.

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1 Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University , Tokyo, Japan .
2 Department of Cardiology, Tokyo Women's Medical University , Tokyo, Japan .
3 Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo , Tokyo, Japan .
4 School and Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology , Yokohama, Japan .


Pluripotent stem cells, including induced pluripotent stem (iPS) cells, are promising cell sources for regenerative medicine to replace injured tissues, and tissue engineering technologies enable engraftment of functional iPS cell-derived cells in vivo for prolonged periods. However, the risk of tumor formation is a concern for the use of iPS cells. Bioengineered tissues provide a suitable environment for cell survival, which requires vigorous efforts to eliminate remaining iPS cells and prevent tumor formation. We recently reported three iPS cell elimination strategies, including methionine-free medium, TRPV1 activation through 42°C cultivation, and dinaciclib, a cyclin-dependent kinase 1/9 inhibitor. However, it remains unclear how many iPS cells in bioengineered tissues can be eliminated using these strategies alone or in combination, as well as the mode of subsequent tumor prevention. In the present study, we found that 2 days of cultivation at 42°C sufficiently eliminated 1 × 102 iPS cells in fibroblast sheets and prevented tumor formation. After screening for suitable combinations of these strategies based on Lin28 expression in co-cultures of fibroblasts and 1 × 104 iPS cells, we found that 1 day of cultivation at 42°C in methionine-free culture medium with or without dinaciclib remarkably decreased Lin28 expression and prevented tumor formation. Furthermore, these culture strategies did not affect spontaneous beating or the cell number of human iPS cell-derived cardiomyocytes. These quantitative findings may contribute to decreasing tumor formation risk and development of regenerative medicine using iPS cells.


42°C culture; cell sheet; iPS cell; methionine; tumor

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