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Fat May Serve a Purpose in Stem Cell Research

Weight Loss Surgery Channel, February 26, 2010

Scientist Dr. Joseph Wu at the Stanford University School of Medicine has recently published a new and improved method to generate stem cells "artificially".  For almost a decade there has been substantial controversy regarding the use of embryonic stem cells, with the debate becoming socially and politically focused as opposed to based on science: one camp believing that embryonic stem cell research must be supported at all costs, the other camp believing that adult stem cells can do anything that embryonic stem cells can do, so there should be no research performed in this area.  This debate became somewhat irrelevant when the Japanese group of Yamanaka discovered a method of "dedifferentiating" adult cells into cells that appear at a molecular and functional level similar to embryonic stem cells.  These "artificial" stem cells, called inducible pluripotent stem cells (iPS) have several unique properties:  They don't need to be extracted from embryos; they can be made from the same patient that they will be used on; and the methods of manufacturing can be relatively standardized. 

To date these cells have been demonstrated to be capable of generating not only every tissue in the body tested, but they also can improve disease conditions in animal models ranging from heart attacks, to liver failure, to bone marrow reconstitution.  Unfortunately the biggest problem with iPS cells is that they are difficult to generate.  In order to understand this, it is important to first mention how the cells are made.  Adult cells have the same DNA blueprint as embryonic stem cells.  However in adult cells certain portions of the DNA are not used to make proteins.  So in liver cells the DNA that encodes for proteins found in the skin is "silenced" or "blocked" from making proteins by various chemical modifications that occur as a cell is maturing.  Embryonic stem cells are considered "blank slate" cells because the DNA is capable of expressing every protein found in the body.  In order to make an adult stem cell "younger" so as to resemble an embryonic stem cell, it is necessary to somehow reprogram the DNA in order to allow it to express every gene.  So how would one go about doing this? There is one biological condition in which adult cells take the phenotype of younger cells.  This is in cancer.  This is the reason why some types of cancer start expressing proteins that other cells normally produce.  For example certain liver cancers can produce insulin, even though liver cells do not produce insulin.  The concept that certain cancer genes can evoke a "rejuvenation" of adult cells was used by Yamanaka as a starting point.  His group found that if you insert the oncogene c-myc, together with the stem cell genes Nanog, Oct-4, and SOX-2 skin cells will start to look like embryonic stem cells.  If these cells are placed on top of feeder cells then they can be expanded and used as a substitute for embryonic stem cells.

The current problem with wide-scale use of this approach is that insertion of the various genes into the cells requires the use of viruses that literally infect the cells with the foreign genes.  Not only can the viruses cause cancer, but also the genes administered can cause cancer because they are oncogenes.  The other hurdle is that generation of iPS cells is a very inefficient process.  It takes approximately 2-3 months to generate stable cells, and these cells are usually generated from approximately 1 out of 100-300,000 starting cells.  We previously discussed advances that allowed for uses of non-hazardous means of inserting genes into cells to make iPS http://www.cellmedicine.com/thomson-safer-ips.asp , in this current article another approach was described to increase efficacy.

Scientists used as starting population not skin cells, which are considered substantially differentiated, but instead used fat derived stem cells.  This type of stem cell is very much a mesenchymal stem cell http://www.youtube.com/watch?v=qJN2RyBj78I and possesses ability to transform into different tissues already.  Thus by starting with a cell that is already more "immature", scientists have been able to increase the rate of iPS generation, as well as, alleviate the need for the oncogene c-myc.

Other approaches being investigated on increasing generation of iPS cells include use of chemicals that affect the DNA structure such as valproic acid.  This is interesting because simple administration of valproic acid on bone marrow stem cells has been demonstrated to increase their "stemness" http://www.youtube.com/watch?v=3Hc4LCUOSiA .

Although we are still far from the day when individual-specific stem cells will be available for widespread use, we are getting closer to this dream at a very fast pace.



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