intrinsic to the IPSC generation process may pose risk of enhancing

Intrinsic to the ipsc generation process may pose

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intrinsic to the IPSC generation process may pose risk of enhancing tumorigenesis through both the introduced genes themselves and in theory via the potential changes at specific integration sites. The IPSC field is evolving rapidly and moving away from methods of induction that rely on genetic changes. This approach is in its early days with some very promising initial results [30, 31], but predictions are that such a move gener- ally should reduce tumorigenicity and improve safety. How- ever, important questions remain. Will it ever be possible to make IPSC with absolutely no genetic changes? Can IPSC ever totally escape from dependence (whether via genetic or nongenetic approaches) on Myc, KLF4, and other possible oncogenes? Although it may appear that the IPSC field has al- ready answered this affirmatively for Myc in that IPSC can be generated without added Myc, the omission of Myc reduces the efficiency of IPSC generation and yet these IPSC can still produce tumors in the form of teratoma [20, 21, 32]. These studies also do not address the role of endogenous Myc. In IPSC generated without genetic addition of Myc, the cells of origin may well be characterized by unusually high levels of endogenous Myc proteins required for the reprogramming and could make the cells prone to tumorigenesis. P ROPOSING AN A LTERNATE A SSAY OF T UMORIGENICITY FOR IPSC AND O THER S TEM C ELLS To gauge the tumorigenic nature of IPSC most often research- ers have used what will be termed the derived mouse assay. In this assay, through mouse genetics IPSC are used to con- tribute to the formation of chimeric mice in which some tis- sue lineages are derived from IPSC. The mice are then stud- ied for tumor development. Using this assay, IPSC have been reported to cause malignant tumors in up to 20% of such derived mice [5], whereas IPSC generated without exogenous Myc have been reported to not form tumors [20, 32]. The Figure 1. The relationship between pluripotency and tumorigenicity. Biological (top) and molecular (bottom) links between pluripotency and tumorigenicity are described. Abbreviations: EC, embryonic carcinoma cells; hESC, human embryonic stem cells; IPSC, induced pluripotent stem cells. 1052 Confronting the Stem Cell Tumorigenicity Problem
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cause of the tumors has been thought to be most often due to reactivation of Myc from previously silenced viral insertions. The problems with the derived mouse assay are twofold. First, the IPSC must go through early embryogenesis and are sub- ject to the powerful embryonic reprogramming forces that are predicted to dramatically reduce the apparent tumorigenicity of the cells. Second, the derived mouse system for studying IPSC tumorigenicity bears no resemblance to how cells would be used in regenerative medicine where they would either be focally injected in a site to be repaired or administered intra- venously (IV). Both focal injection and IV administration of IPSC as a means for studying IPSC tumorigenicity have not been reported in the literature. Unfortunately, these assays are expected to show higher rates of tumorigenicity than the derived mouse assay, but more accurately reflect
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