Why are pluripotent stem cells falling short of expectations?

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There has been a lot of research over the last few years focused on turning adult stem cells into induced pluripotent stem cells (iPS cells). This was originally accomplished by using viral vectors to introduce reprogramming genes into these cells (reference). Because these reprogramming genes can also induce cancer and activate thousands of other “superfluous” genes, methods were introduced to initiate an internal activation of these genes without the need for viral vectors.  Even so, problems still persist. A  2010 article describes the apparent inability of these procedures to generate stable, long-term viable cell lines that can be used as substitutes for embryonic cell lines.  So the question that remains is why?

The focus of my studies on eukaryotic DNA superstructure suggest that during the conversion of embryonic cells into stem cells, DNA is being lost in the form of small replicons similar to transposons. Unless this DNA is returned to the cell in the same position from which it was lost, there can be no true reversion of stem cells into embryonic cells. Furthermore, DNA replicons may be fusing together as well during differentation, leading to a small loss of genetic information. However, it is possible that these  phenomena are localized based upon the kind of stem cells being generated during embryogenesis. This would mean that the genome exists as compartments, most of which remain genetically unaltered as condensed chromatin during the course of stem cell formation. A blood stem cell, genetically altered to prevent it from forming all blood cell types may not be similarly altered in its ability to form other kinds of cells like hepatocytes, etc. When these stem cells are reprogrammed, the condensed chromatin is released, making available other compartments for differentation of new tissue types unrelated to blood. The result is a cell that has become genetically altered in more than one compartment, and the original genetically altered compartment may become condensed so that it is unavailable for gene expression (or not).  In the latter case, the iPS cell would behave as a chimera, trying to behave as two different kinds of stem cells. This alone may have an impact on their clinical utility.

It is well known that DNA circular deletions and rearrangements occur on a wide scale during B cell differentation. There is no reason to assume that similar but more subtle alterations aren’t also occurring throughout the rest of the genome during the course of cellular differentation.


About frankabernathy

I am a retired cell biologist and alumnus of Ohio State University. I became interested in chromosomes as far back as the 1960's when I wrote a term paper on the effects of radiomimetic drugs on chromosomes. I was fascinated at how they could break apart and reform new structures so easily. I became further involved in the early 1970's after taking a cytogenetics course at the University of Arkansas. I took that knowledge with me to Ohio State in 1980 where I eventually worked on my research and completed my Ph.D. dissertation, "Studies on Eukaryotic DNA Superstructure". My studies and later research suggested that the DNA within the eukaryotic chromosome is not the simple, linear molecular thread so widely suggested in all the classic textbooks published today. Instead, it may be the culmination of a geologically rapid set of endosymbiotic events where microorganisms plug into each other to create something greater than themselves. Feel free to contact me at fabernathy@sbcglobal.net.
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