Induced Pluripotent Stem Cells (iPS) from Human Skin: Probable Replacement for Embryonic Stem Cells
by Rich Deem

Introduction

iPS Stem Cells

The announcement of the ability to produce embryonic cell-like lines from ordinary skin cells has the news media scrambling to get feedback about the possible efficacy of such lines in stem cell therapies. Many politicians have landed on one side or the other, with liberals saying that embryonic stem cell research is still necessary1 and conservatives claiming that all embryonic research should be halted. The marketplace of science will eventually weigh-in on which method(s) are used in real therapies.

Rich Deem

Embryonic stem cell (ESC) research has been a hot topic, with conservatives saying that such research is morally unacceptable and liberals saying that conservatives value a clump of cells more than people who have serious disabling diseases. Three separate groups of medical researchers recently showed that normal skin cells can be reprogrammed to an embryonic state, producing what are now called induced pluripotent stem (iPS) cells. Originally performed in mice in June, 2007,2 researchers took four genes OCT3/4, SOX2, KLF4, and c-MYC and incorporated those genes into the nucleus of cells to induce pluripotency. Such lines could be expanded indefinitely and could differentiate to form numerous kinds of different tissues.

Human iPS cells

Just five months after the mouse study was published, the feat was repeated by three separate laboratories using human skin cells.3 One research group used the same genes as those used in the mouse study, whereas a second group used OCT3, SOX2, NANOG and LIN28. The techniques were efficient enough to generate one cell line for every 5-10 thousand cells treated. Although not extremely efficient, it is quite usable, since it is possible to obtain hundreds of thousands to millions of cells to carry out these kinds of studies. The technique was recently replicated for adult human skin cells,4 instead of skin cell lines, demonstrating that it could be used to generate patient-specific cell lines.

Do iPS = ESC?

Studies using iPS cell lines have shown that those cells undergo similar changes compared to what is observed with embryonic stem cells. Cell populations grew at the same rate, telomerase (which preserves the ends of chromosomes) was present in both iPS and ESC. Several genes that are silenced in fibroblasts, but active in ESC, were also active in the iPS cells. The iPS cell lines could be differentiated into heart muscle and neuronal cells, in addition to basic cell types (ectoderm, mesoderm, and endoderm). Gene expression assays showed that 5,000 genes from iPS cells showed a five-fold difference in expression compared to those in fibroblasts, although 1,267 genes had a five-fold difference in expression between ESC and iPS cells. According to the James Thompson study, "The human iPS cells described here meet the defining criteria we originally proposed for human ES cells (14), with the significant exception that the iPS cells are not derived from embryos."

Downsides/Problems

The new technique is not without its own set of problems, although some of those have already been resolved. One of the original genes used for reprogramming (c-MYC) has been shown to produce tumors and cancers. Obviously, it would not be a good choice for patient therapy. However, this gene has been eliminated in some of the newly published techniques.5 The second problem is that the genes are introduced through the use of a retrovirus that incorporates into the host cell DNA. Depending upon where the gene sequence inserts, it may cause trouble (including cancers). Those who watched the I am Legend movie will remember that a retrovirus-derived cancer treatment was responsible for turning the surviving members of the human race into an army of grotesque monsters. Although such a transformation is not possible, the initiation of cancer in even a small number of treated patients would make such treatments unusable for human therapy. Alternatives to the use of retroviruses do exist, although they are not as efficient. The ideal method would involve direct reprogramming of the necessary genes, instead of adding additional copies of those reprogrammed genes.

Conclusion Top of page

Induction of pluripotency to produce embryonic-like stem cells is the hot topic in stem cell research. The fact that iPS cells have been produced in at least three different laboratories within a few months after the initial animal studies shows that the technique is robust and easily reproducible. In contrast, the competing technique, human somatic cell nuclear transfer (cloning), has never been transferred from animal studies to human application, despite years of attempts. At this point, it seems pretty certain that the iPS technique will soon replace ESC as the preferred means of generating human stem cell lines.



References Top of page

  1. In response to the announcement Democrat Senator Tom Harkin of Iowa said ,"Our top researchers recognize that this new development does not mean that we should discontinue studying embryonic stem cells. Scientists may yet find that embryonic stem cells are more powerful."
  2. David Cyranoski. 2007. Simple switch turns cells embryonic Technique removes need for eggs or embryos. Nature doi:10.1038/447618a.
  3. Gretchen Vogel 2007. Researchers Turn Skin Cells Into Stem Cells. ScienceNOW Daily News 20 November 2007
    Yu, J., M. A. Vodyanik, K. Smuga-Otto, J. Antosiewicz-Bourget, J. L. Frane, S. Tian, J. Nie, G. A. Jonsdottir, V. Ruotti, R. Stewart, I. I. Slukvin and J. A. Thomson. 2007. Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells. Science DOI: 10.1126/science.1151526.
    Takahashi et al. 2007. Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors. Cell doi:10.1016/j.cell.2007.11.019.
  4. In-Hyun Park, I., R. Zhao, J. A. West, A. Yabuuchi, H. Huo, T. A. Ince, P. H. Lerou, M. W. Lensch and G. Q. Daley. 2007. Reprogramming of human somatic cells to pluripotency with defined factors Nature doi:10.1038/nature06534.
  5. Nakagawa, M., M. Koyanagi, K. Tanabe, K. Takahashi, T. Ichisaka, T. Aoi1, K. Okita, Y. Mochiduki, N. Takizawa and S. Yamanaka. 2007. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. doi: 10.1038/nbt1374


Last Modified December 27, 2007