Breakthroughs in stem cell biology: Human iPS cells
by M. William Lensch, Ph.D.*

Three groups have reported that, they can create cells very similar to human embryonic stem (ES) cells starting from human skin cells (Takahashi et al., 2007; Yu et al., 2007; Park et al., 2008). These engineered cells are termed "induced pluripotent cells" or iPS cells where pluripotency describes the ability to develop into all tissues of the body. The work builds upon similar data obtained using mouse cells (Read the Briefing; Maherali et al., 2007; Okita et al., 2007; Takahashi and Yamanaka, 2006; Wernig et al., 2007), and is significant in that it shows that non-embryonic cells are capable of being "pushed backwards" developmentally to a state that is very similar to ES cells. While human iPS cells are not exactly the same as human ES cells, they nevertheless point the way to an exciting future in stem cell biology and regenerative medicine for at least three reasons:

            First, to generate human iPS cells, a relatively simple mix of four genes was required, though a slightly different combination was used by the different groups. It is unclear how each of the genes used functions to create ES-like cells and future projects will no doubt address this question in an effort to gain greater insights into developmental biology as well as to perfect the technique's efficiency and safety for potential clinical use.

            Second, the system may enable the production of pluripotent cells with a certain genetic makeup. This would be very important in the study of human genetic diseases where a skin biopsy from an affected patient could be used to generate an ES-like cell line to study how certain mutations impact the abnormal formation or maintenance of tissues Furthermore, additional refinement of this approach might one day allow the generation of patient-specific pluripotent cells that, in turn, could be used to generate mature cell types which would not be rejected by the patient's immune system after transplantation. While this work is preliminary and requires much improvement prior to any future clinical application it remains exciting as an avenue of exploration towards both of these ends.

            Third, the iPS process requires neither embryos nor egg cells and thus may prove to be less controversial that hES cell research and nuclear transfer (NT). That said, it is important to point out that iPS cells are possible only because of information gleaned from prior studies using both ES cells and NT. Thus, some individuals considering hES cell and NT research to be ethically problematic may likewise consider iPS work to be ethically tainted. Furthermore, the methods used to create iPS cells require a great deal of refinement and will undoubtedly require additional comparisons to existing and future embryo-derived cells as they are the gold-standard for pluripotent cells. The most efficient course ahead will be one permitting research using hES, NT, and iPS cells wherever each is best indicated.

            A lot remains to be learned in the field of pluripotent cell biology and iPS cells put more questions on the table. Chief among them is how are four genes able to push skin cells back to pluripotency? What other genes are influenced by the four iPS genes and how in turn are those genes regulated? Also, can the process be refined in a manner that makes it safe for clinical application? The answers to these and other questions await the results of future experiments. It is truly an exciting time to be a stem cell scientist.

*Author Affiliation
M. William Lensch, Ph.D.
Instructor in Pediatrics, Children's Hospital Boston
Boston, USA

Notes:
Read the Briefing on the generation of mouse iPS cells

Bibliography:

Lensch, M. W., and Daley, G. Q. (2006). Scientific and clinical opportunities for modeling blood disorders with embryonic stem cells. Blood 107, 2605-2612.

Maherali, N., Sridharan, R., Xie, W., Utikal, J., Eminli, S., Arnold, K., Stadtfeld, M., Yachechko, R., Tchieu, J., Jaenisch, R., et al. (2007). Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1, 55-70.

Okita, K., Ichisaka, T., and Yamanaka, S. (2007). Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317.

Park, I. H., Zhao, R., West, J. A., Yabuuchi, A., Huo, H., Ince, T. A., Lerou, P. H., Lensch, M. W., and Daley, G. Q. (2008). Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141-146.

Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872.

Takahashi, K., and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676.

Wernig, M., Meissner, A., Foreman, R., Brambrink, T., Ku, M., Hochedlinger, K., Bernstein, B. E., and Jaenisch, R. (2007). In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318-324.

Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., Nie, J., Jonsdottir, G. A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.

Posted February 27, 2008

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