Induced Pluripotent Stem Cells

IN STEM CELL jargon, a totipotent stem cell is one that arises very early in development and is capable of generating both extra embryonic (e.g., placenta) and embryonic tissues. In humans these totipotent stem cells are only found during the first few divisions of the fertilized egg. From the inner cell mass, pluripotent stem cells can be isolated that are able to produce any cells within the body. Until very recently, these could only be isolated from early embryos. However, a new technique pioneered by a group in Japan now allows pluripotent stem cells to be generated from adult cells within the body. This work was based on the idea that any cell in the body can be “reprogrammed” to a more primitive state, and was first proven through the cloning of Dolly the sheep. The term for these new reprogrammed pluripotent cells is induced pluripotent stem cells.

The power of induced pluripotent stem (IPS) cells is that they do not require the destruction of embryos and they may one day be produced from the patient's own adult cells, allowing the generation of perfectly matched tissues for transplantation therapies. However, in some cases where there is a genetic disease, the IPS cells may have the same deficit. Pluripotent stem cells were first induced in murine cells in the year 2006 and in human cells one year later. Thus the technology is still quite new and much research is still warranted. To date, in all characteristics the IPS cells resemble true pluripotent stem cells in all respects tested.

To induce a pluripotent stem cell, scientists introduce spécifie pluripotency genes into non—plu-ripotent cells, such as fibroblasts. These pluripo—tentcy genes include two very important transcription factors known to maintain mouse and human embryonic stem cells in a primitive state—Oct-4 and Sox-2. Fibroblasts are cells that produce and secrete the fibrous extracellular matrix that holds cells together in the body. The vector to introduce these genes into a non—pluripotent cell is called a retrovirus. The retrovirus does not have any viral [Page 260]capacity except that it can enter the cells easily and the genes it carries are thus accessible to the cell.

Hierarchy of stem cells. Induced pluripotent stem cells may one day be produced from a patient's own cells, allowing the generation of perfectly matched tissues for transplantation therapies.

The first research laboratory to show induction of pluripotent stem cells in the mouse was a Japanese group led by Dr. Shinya Yamanaka at Kyoto University. This work was performed in mouse cells and published in 2006. In 2007 the Yamanaka group and other independent American labs showed a more advanced technique for inducing mouse pluripotent stem cells. However, one of the introduced genes (cMyc) caused cancer one—fifth of the time when the IPS cells were introduced into test mice. The Yamanaka group then developed IPS cells without using this gene and the resulting mice did not develop cancer. Later that year, the same group at Kyoto University, and independently a group led by Dr. James Thomson at the University of Wisconsin, Madison, created IPS cells from human fibroblasts. The two groups used overlapping sets of genes, in particular both Oct-4 and Sox-2.

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