Induced Pluripotent Stem Cells and Their Importance

Induced Pluripotent Stem Cells and Their Importance
by Wise Young, PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey
Piscataway, NJ 08854-8082

11 December 2008

Induced pluripotent stem (IPS) cells hit the scientific scene two years ago and have since taken the stem cell field by storm.  Although many scientist predicted our ability to make stem cells as we learn more about stem cells, IPS cells are being used by opponents and advocates to argue for and against embryonic stem cell research.  In this article, I will try to explain why IPS cells are important and that it is not yet time to put away the stem cell research advocacy banner.

IPS cells are stem cells derived from another cell, typically an adult somatic cell, by forcing the expression of certain genes.  In 2006, Shinya Yamanaka at Kyoto University reported making such cells from mouse skin cells (fibroblasts) by inducting the cells to express four genes.  In June 2007. Yamanaka’s group and two other groups successfully made and implanted IPS cells into developing mice, produce chimeric animals that consisted of cells made by host and the implanted IPS, confirming the pluripotency of the cells.

In November 2007, Yamanaka’s and Jamie Thomson’s group in Wisconsin simultaneously published studies showing that IPS cells can be made from human skin cells.  Yamanaka inserted four genes, i.e. Oct3/4, Sox2, Klf4, and cMyc, by retrovirus into human fibroblasts while Thomson, et al. inserted Oct4, Sox2, Nanog, and Lin28 using lentivirus.

Advocates of embryonic stem cell research triumphantly pointed to these findings as important fruits of the research.  Opponents to the research say that the findings eliminate the need to do embyronic stem cell research.  Others point out that much work still needs to be done before IPS cells can be used clinically and that study of embryonic stem cells must go on even if IPS cells were useful for therapeutic purposes.

More than Pluripotent

Many scientists, including myself, predicted as long as a decade ago that we should one day be able to make any cell into a stem cell.  Stem cells are of course just cells expressing certain genes.  Thus, it was just a matter of time before we knew what genes were responsible for “stem-ness” and would be able to make stem cells from somatic cells by expressing these genes.

However, few of us imagined that becoming a stem would require just four genes expressed at the same time.  It could have been much more difficult.  In fact, several combinations of four genes appear to work.  Both Yamanaka and Thomson used Oct and Sox genes but Yamanaka used Klf4 and cMyc while Thomson used Nanog and Lin28.

IPS cells are also more than pluripotent.  They not only make themselves and a variety of cells in culture but, when the cells are placed into developing fetuses, they contribute to the creation of chimeric animals.  This means that the cells are able to respond appropriately to signals of the body to produce all the different kinds of the cells of the body.

Caveats for Clinical Use

Both Yamanaka and Thomson used viruses to inset the genes into the cells.  Yamanaka used retrovirus while Thomson used lentivirus.  Both of these viruses insert genes into the genome, at random locations, posing a significant risk of damaging existing genes and possibly resulting in abnormal and possibly even cancerous cells.  For this reason, several groups immediately worked on alternative approaches to inserting the genes.

Konrad Hochedlinger at Harvard used adenovirus to modifiy mouse fibroblasts and liver cells into IPS cells.  Adenovirus does not insert the genes into the genome and therefore poses less danger of creating tumors.   The resulting cells were pluripotent but the technique has not yet be tried on human cells.  In the meantime, Yamanaka was able to insert the genes with a plasmid, without a virus, albeit at very low efficiency.

Finally, the genes themselves may pose problems.  In the case of the four genes used by Yamanaka, c-Myc is a proto-oncogene that has long been associate with cancer.  Thomson used the LIN28 gene in place of c-Myc.  This is an mRNA binding protein expressed in embryonic stem cells and embryonic carcinoma cells, associated with proliferation.  Only experience and time will determine whether cells induced by these genes are safe.

Embryonic Stem Cell Research is Still Needed

Some people concluded that the discovery of IPS cells eliminates the need for embryonic stem cell research.  In my opinion, this conclusion is premature.  While IPS cells appear to have many of the characteristics of embryonic stem cells, they are not necessarily the same.  However, it is reasonable to ask why embryonic stem cell research is necessary once it is possible to derived pluripotent stem cells from somatic cells?

The reason for studying embryonic stem cells was never just a potential cell source for therapies.  Studying embryonic stem cells is critical to the study of developmental biology.  Even though Yamanaka’s and Thomson’s studies have shown that expressing four genes are sufficient to produce pluripotental embryonic-stem-cell-like IPS cells, we have little idea why they do what they do.

We must continue to be study embryonic stem cells.  The discovery of IPS cells, however, has reduced the pressure to harvest embryonic stem cells from discarded blastocysts.  Because growing embryonic stem cells is difficult and creation of IPS cells is easy, many laboratories are switching to studying IPS cells.  But, this does not mean that embryonic stem cell research can stop.  There is still much to be learned.

Implications of IPS cells for Therapy

The discovery of IPS cells has transformed the field.  The central problem in cell transplantation therapy is the creation of immune-compatible cells for transplantation.  For a decade, the only solution was to clone cells.  Embryonic stem cells can be cloned by inserting a somatic cell nucleus into an egg and inducing the egg to develop and produce embryonic stem cells and other cells.

Cloning by somatic cell nuclear is extremely difficult and laborious.  It requires first the creation of a egg with a somatic nucleus.  The egg must then be stimulated to develop into a blastocyst.  An embryonic stem cell line must then be isolated and grown from cells collected from the blastocyst.  That cell line must then be assessed and expanded.  This is a expensive procedure that may cost over US$1,000,000 per validated cell line.

Less than two years after the first discovery of IPS cells, many laboratories have shown that creatng IPS cells is fast, easy, and reliable.  In fact, it may be faster and easier to create new cell lines to study than it is to grown and maintain existing lines of embyronic stem cells.  While many safety studies still need to be done, there is no question in my mind that IPS cells will be the cells of the future.

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