Response to Letters from Daley et al. and Ellis et al.

We appreciate the support from both sets of authors (Daley et al., 2009xDaley, G.Q., Lensch, M.W., Jaenisch, R., Meissner, A., Plath, K., and Yamanaka, S. Cell Stem Cell. 2009; 4: 200–201Abstract | Full Text | Full Text PDF | PubMed | Scopus (81)See all References, Ellis et al., 2009xEllis, J., Bruneau, B.G., Keller, G., Lemischka, I.R., Nagy, A., Rossant, J., Srivastava, D., Zandstra, P.W., and Stanford, W.L. Cell Stem Cell. 2009; 4: 198–199Abstract | Full Text | Full Text PDF | PubMed | Scopus (53)See all References) in our efforts to propose guidelines for the generation and characterization of iPSCs and for raising additional valuable points that increase the breadth of our review.A major goal of our Protocol Review was to propose a common set of criteria for the characterization of iPSCs in an emerging field, through direct comparison with our knowledge of ESCs, which represent the best characterized pluripotent cell type.We acknowledge the existence and value of other pluripotent cell populations, such as EpiSCs and FAB-SCs, that do not fulfill all criteria of pluripotency such as germline transmission. If it is possible to derive pluripotent cell lines akin to EpiSCs and FAB-SCs directly from somatic cells, it may be helpful to introduce new nomenclature to distinguish them from conventional iPSCs. This will also necessitate a dynamic development and continuous reflection of the criteria used to define iPSCs as well as other induced pluripotent cell populations.We agree with Ellis et al. that the use of in vitro assays to assess the differentiation capacity of iPSCs is a powerful approach for the development of directed differentiation protocols; for example, cell-type-specific tests such as transplantation can provide more detailed information on functional differentiation capacity than that offered by teratoma formation. However, since in vitro assays are often more difficult to perform and standardize, we concur with Daley et al. that a common assay such as teratoma formation is still warranted, particularly when the intention is to simply verify pluripotency of iPSCs.The availability of reporter constructs is certain to advance progress in the field, and their use in the experimental applications mentioned by Ellis and coauthors should be encouraged. We would like to reaffirm, however, that the use of transgenic reporters as surrogate markers for reprogrammed cells should be approached with caution, so as not to equate reporter-expressing cells with genuine iPSCs which can misguide interpretation of optimization procedures for iPSC derivation.In conclusion, we thank both groups of authors for their constructive comments on our Protocol Review and welcome further discussion of the criteria for iPSC characterization as the field advances and our knowledge of pluripotent cell populations increases. In order to bring consistency to the field and enable cross-lab comparisons of iPSC derivation protocols, we encourage our colleagues with extensive experience in deriving pluripotent cells to convene a taskforce to collaboratively develop consensus standards by which the field may assess existing and future lines.