Cartilage tissue engineering identifies abnormal human induced pluripotent stem cells

Human induced pluripotent stem cell (iPSC) technology has great potential for cell therapy1,2; however a risk of tumorigenicity has been identified. Indeed, incidents of tumor formation have been observed in chimeric mice derived from mouse iPSCs due to the presence of the pro-oncogene, c-MYC, in reprogramming3,4,5. In the undifferentiated state, the pro-oncogenic nature of iPSC lines is not entirely predictable as global gene expression patterns and their epigenetic state in iPSCs are similar to that in embryonic stem cells (ESCs)6,7. Like ESCs, when iPSCs are transplanted into animals, they will form teratomas; however, teratoma formation cannot predict the pro-oncogenicity of select iPSCs. Currently, chimera formation in mouse is a reliable approach to identify pro-oncogenic iPSCs, but this method cannot be practiced using human iPSCs. In addition, tests in animal models can be time consuming. For example teratoma formation, which is not a test for oncogenic potential can take between one and ten months8. Therefore, a quick and reliable surrogate test for oncogenicity in human iPSCs needs to be developed. The in vitro differentiation of iPSCs may provide an alternative approach to evaluating tumorigenic risk. We have focused on using cartilage tissue engineering as a differentiation model for ESCs, since functional 3D cartilage tissues can be formed in vitro with simple and robust protocols9,10. Unique and uniform morphology of cartilage tissue helps to identify any abnormal cell growth or differentiation by histological analysis. Here, we report that cartilage tissue engineering using iPSCs is an excellent method for identifying cell lines, which display abnormality during differentiation.