Induced pluripotent stem cells – second-rate stem cells so far

I have reported on Induced pluripotent stem cells (iPSCs) in my treatise and in numerous past blog entries(ref)(ref)(ref).  I have viewed these cells as probably providing  the golden keys to closing the loop on the stem cell supply chain allowing extension of human longevity(ref)(ref)(ref).  iPS cells can be created by forcing expression of certain genes in normal somatic (body) cells taken from an individual, like skin cells.  According to most of the literature until recently such cells are pluripotent  like human embryonic stem cells (hESCs), and can be induced to differentiate into any cell type.  They seemed to offer a better alternative for stem cell therapies than use of hESCs because they are autologous, i.e. derived from the same individual they are used on and therefore not subject to immune system rejection.  

As more research on iPSCs is being done, however, evidence has been building that the iPSCs that have been created so far are second-rate in a couple of key respects and so-far unfit for use in human therapies. 

The February 2010 study Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency looks at the differentiation of iPSCs into neural cells.   “For the promise of human induced pluripotent stem cells (iPSCs) to be realized, it is necessary to ask if and how efficiently they may be differentiated to functional cells of various lineages. Here, we have directly compared the neural-differentiation capacity of human iPSCs and embryonic stem cells (ESCs). We have shown that human iPSCs use the same transcriptional network to generate neuroepithelia and functionally appropriate neuronal types over the same developmental time course as hESCs in response to the same set of morphogens; however, they do it with significantly reduced efficiency and increased variability. These results were consistent across iPSC lines and independent of the set of reprogramming transgenes used to derive iPSCs as well as the presence or absence of reprogramming transgenes in iPSCs. These findings, which show a need for improving differentiation potency of iPSCs, suggest the possibility of employing human iPSCs in pathological studies, therapeutic screening, and autologous cell transplantation.”  The study was authored by Su-Chun Zhang and colleagues.  Su-Chun Zhang has published previous studies related to creating neural cells from stem cells such as the 2009 article Differentiation of spinal motor neurons from pluripotent human stem cells.   

I do not think these findings are very surprising since iPSCs are reverted from mature cells and may have short telomeres.  In other words, though newly-created iPSC cells can differentiate into any cell type like embryonic stem cells can, unlike embryonic stem cells the iPSCs made so far are mostly old and tired cells from the viewpoint of replicative potential.  I covered this point in the blog entry Telomeres and telomerase in Induced Pluripotent stem cells – not what we thought.  That blog entry cites the March 2010 publication Spontaneous reversal of the developmental aging of normal human cells following transcriptional reprogramming.  That new study contradicts what had been the prevalent assumption that reverting a cell to iPSC status restores the expression of telomerase and telomere length to equivalent embryonic stem cell length.  This study asserts that reverting a mature cell to iPSC status does not automatically restore its telomere lengths to those found in hESCs.  “Conclusion: Prematurely aged (shortened) telomeres appears to be a common feature of iPS cells created by current pluripotency protocols. However, the spontaneous appearance of lines that express sufficient telomerase activity to extend telomere length may allow the reversal of developmental aging in human cells for use in regenerative medicine.”   

Put differently, the March 2010 study says restoring a cell to pluripotency and providing the cell with youth are two quite different things and the former does not necessarily imply the latter.  Pluripotency of an iPSC implies that, like an embryonic stem cell, the iPSC can differentiate into any somatic cell type.  Absence of youth in this case means that the restored iPSC cell could probably not lead to many generations of descendents like an embryonic stem cell could,  because its telomere lengths are short like those in old cells.   In fact, iPSC cells can be near senescent.  The February 2010 Su-Chun Zhang article does not link the observed variability and inefficiency of iPSC differentiation for generating neural cells to short telomeres, but it seems to me that the association may be a key one.   

This question of telomere lengths of iPSCs, nonetheless, appears to be somewhat controversial.  The above-cited publication directly contradicts assertions in a number of earlier publications including the 2009 publication Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells.  That report asserted “We show here that telomeres are elongated in iPS cells compared to the parental differentiated cells both when using four (Oct3/4, Sox2, Klf4, cMyc) or three (Oct3/4, Sox2, Klf4) reprogramming factors and both from young and aged individuals. We demonstrate genetically that, during reprogramming, telomere elongation is usually mediated by telomerase and that iPS telomeres acquire the epigenetic marks of ES cells, including a low density of trimethylated histones H3K9 and H4K20 and increased abundance of telomere transcripts.” 

It seems to me that it is essential to develop reliable techniques for creating iPSCs with long telomeres, perhaps by selecting mutant lines that naturally express telomerase.  That may go a long ways to correcting the problems of lack of differentiation capability and wide variability noted by Su-Chun Zhang and his colleagues.  Or, it might be necessary to address additional issues to get iPSCs to behave as well as hESCs.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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4 Responses to Induced pluripotent stem cells – second-rate stem cells so far

  1. prophets says:

    it will sure be interesting to see if they ever get iPSCs working like we want it to. i have a feeling we will be looking at this sort of puzzle for the next twenty to thirty years.

  2. admin says:


    Well, you may well be right but at my age I prefer to be an optimist. I suspect it will not be too tough to revert iPSCs in a way that they express lots of telomerase and have long telomeres like hESCs, which I think is more of a technical issue than an in-principle one. Then the question will be whether they are as reliable and ready to differentiate as ESCs. A very interesting thing covered in the second paper by Su-Chun Zhang that I mentioned is that he seems to have worked out a reliable procedure for getting pluripotent stem cells to differentiate into different neural cell types – an important feat.

    On one level you are sure to be right. Whatever we know or can be done now will prove to be very crude compared to what will be known and can be done in twenty years.


  3. dima says:

    .Thank you for your excellent review. Alas, the problem is much more complicated. Even in the case of successful solution of the problems mention in your review we stillhave a problem of different response of adult organism (teratoma or teratocarcinoma formation) and embryo (normal chimera formation) on ips-cells or embrional cells.( See: Mintz B. Normal mice produced from malignant ter… cells. Proc.Natl.Acad. Sci. USA 72. 3585-3589, 1975 ,; Martin c.r. Science, 209,768-776, 1980 Papaioannou V.E. J. Embriol.Exp.Morphol.,44,93-104,1978 )possibly due to somatic rearrangement of genes in accordance with development program (leading to loss of macroregeneration ability)

  4. admin says:

    Hi dima:

    Yes, thanks for pointing out these issues. The 1975 PNAS citation you mention is fascinating: “Thus, after almost 200 transplant generations as a highly malignant tumor, embryoid body core cells appear to be developmentally totipotent and able to express, in an orderly sequence in differentiation of somatic and germ-line tissues,many genes hitherto silent in the tumor of origin.” There is a formidable latent developmental program.

    The in-vivo issues you point out related to introducing pluripotent cells are real and serious. However, I do think some progress is being made in selected areas, such as in directing differentiation of pluripotent hESCs into neural cells. A search like this one produces a number of relevant research citations.

    “The generation of unlimited numbers of dopamine neurons from mouse embryonic stem cells can be achieved in a multi-step differentiation protocol, allowing the sequential generation of embryonic stem cells, embryoid bodies, early ectodermal cells, proliferating CNS precursors, and differentiated neurons and glia. Alternatively, neural induction and directed differentiation into various neuronal and glial cell types can be achieved by co-culture with bone marrow-derived stromal feeder cell lines such as MS5” from

    There is still a long long way to go but it should be an exciting journey.


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