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New, Improved Method Announced for Creating Induced Pluripotency in Adult Cells

Cell Stem Cell, September 11, 2008

The successful reprogramming of mature, non-stem cell, somatic cells to a more primitive state in which they behave with the same pluripotency as embryonic stem cells, was a major scientific breakthrough that has offered great hope in the field of regenerative medicine. Known as iPS (induced pluripotent stem) cells, these newly formed cells also avoid the ethical dilemmas surrounding embryonic stem cells, since no embryos are required for the generation of iPS cells. However, the conversion of regular somatic cells into iPS cells has been an extremely inefficient process, in addition to dangerous, since the production of these cells involves the use of retroviruses, lentiviruses, adenoviruses and (cancer causing) oncogenes, none of which are allowable for clinical use, and all of which are specifically prohibited by the FDA (Food and Drug Administration) and are grounds for disqualification from the FDA approval process of medical therapies. Furthermore, the precise molecular, genetic and biochemical mechanisms of cellular reprogramming that are at work in the production of iPS cells are still not yet fully understood.

Two independently published papers, however, now signify further progress in the field. A team led by Dr. Konrad Hochedlinger of the Harvard Stem Cell Institute, and another team led by Dr. Rudolf Jaenisch of the Massachusetts Institute of Technology and the Whitehead Institute, have both published findings which corroborate each other's work.

Dr. Hochedlinger's team was able to generate iPS cells with a pluripotency similar to that of embryonic stem cells, not by using the viral and oncogenic vectors that have been previously used, but instead by using the drug doxycycline for reprogramming of the cells. Perhaps of greatest importance, however, was the discovery that after the "primary" iPS cells were allowed to differentiate into mature cells, the researchers then re-exposed the cells to doxycycline a second time, which induced the production of a "secondary" group of iPS cells that was generated even more quickly and efficienty than the "primary" group that was produced after the first exposure.

Dr. Jaenish and his team also addressed the idea of generating a secondary round of iPS cells, in a separate paper wherein they describe experiments in which they were able to derive secondary iPS cells by using doxycycline-inducible transgenes. According to Dr. Jaenisch, "The drug-inducible system we describe represents a novel, predictable, and highly reproducible platform to study the kinetics of iPS cell generation. Furthermore, the genetic homogeneity of secondary cells makes chemical and genetic screening approaches to enhance reprogramming efficiency or to replace any of the original reprogramming factors feasible." Dr. Hochedlinger adds, "The secondary system will enable chemical and genetic screening efforts to identify key molecular constituents of reprogramming, as well as important obstacles in this process, and will ultimately lend itself as a powerful tool in the development and optimization methods to produce human iPS cells."

Both research teams confirmed that generation of the secondary group of iPS cells is faster than the generation of the primary group, although the precise time that is involved depends upon the types of skin cells that are used. Human keratinocytes, for example, were found to take approximately 10 days for production, whereas fibroblasts required several weeks. According to Dr. Hochedlinger, "The fast kinetics of reprogramming observed for keratinocytes suggests that these cells would be useful for development and optimization of methods to reprogram cells by transient delivery of factors."

One problem still remains, however, which is the ability of all iPS cells to cause teratomas, which is a specific type of tumor. By formal definition, any cell which is "pluripotent" is capable of forming a teratoma, and if a cell cannot form a teratoma then it is recognized as not being pluripotent. Exactly how pluripotency in a cell may be turned on or off, like a switch, or controlled to the extent that anyone can guarantee, with 100% certainty, that the cell will not cause tumors when administered to human patients, remains to be seen.

Meanwhile, the ability to produce a "secondary" round of iPS cells, more quickly and efficiently than the first round, via a second exposure to doxycycline, represents a significant and important discovery, as scientists advance one step further along the path of elucidating the complex cellular mechanisms that are at work in reprogramming and differentiation.



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