Rebooting cells and longevity

19. March 2009 by admin.

An amazing discovery is still in the process of being made.  Exposing the DNA of many kinds of body cells to just four transcription-factor proteins causes a cell to lose all memory of what it is and does and become what is called an Induced Pluripotent Stem Cell (iPS cell), a cell very much like an embryonic stem (ES) cell.  It appears that an iPS cell, like an ES cell, is capable of progressively differentiating into any cell type, be it heart, skin, nerve, bone or muscle.  In other words the four proteins reboot the cell into embryonic stem-cell type pluripotency.  The entire history of epigenomic information that cell has inherited from its progenitors over the entire life of the animal is simply wiped out.  This includes not only information about what the cell has become (e.g. a brain neuron or a bone or liver cell) but also the history of experiences inherited from its progenitors going back to the inception of the animal.  This history, expressed via methylated DNA can strongly condition the behavior of the cell.  See the Feb 28 post in this blog on Epigenetics, Epigenomics and Aging.  

The proteins are Oct4, Sox2, Klf4, and c-Myc.  Oct4 and Sox2 are transcription factors known to have to do with ES self-renewal and proliferation.  Klf4, and c-Myc are transcription factors known for their roles in cell proliferation, differentiation and survival and regulating gene expression.  This reprogramming effect was at first reported in 2006 and limited to starting with mouse fibroblast cells carrying engineered selection markers(ref,ref).  Later, the effect was demonstrated using a retrovirus to transport the proteins into the nuclii of mouse cells(ref) without a need for engineered cells.  However, the retrovirus could also inject its own DNA into the chromosomes affected, so the process appeared to be unreliable because it could affect the genome of the cell.  More recently, it has been possible to induce pluripotent stem (iPS) cells from mouse fibroblasts and liver cells by using relatively benign nonintegrating adenoviruses(ref).  It appears in several experiments that the four proteins wipe clean all the lifelong DNA epigenetic modifications that normally occur as a stem cell progressively differentiates into being a very specific kind of body cell, like a hair follicle cell.  “DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells.”

This discovery is still in process because most experimental work so far has been with mouse cells and it is still not known for sure how completely  similar the behavior of iPS and ES are.  Nobody has been able so far to make a mouse out of an iPS cell, for example. The possible implications for regenerative medicine are immense.  The idea is to remove some cells from a person, say a small tube of blood cells, restore these in the lab to being iPS cells and then use these in lieu of ES cells for organ regeneration in that person.  Because the cells are from the same person, there would be no problem of immune system rejection.  Several issues require resolution before this kind of therapy can be practical, however.  First, the pluripotency and safety of using human iPS cells must be confirmed.  There is a possibility that they could contain genetic remnants of the andovirus vector that could create mischief for example.  Second, it is important to find effective ways for introducing the iPS cells into human organs so they achieve the desired results of organ regeneration.  If ES or iPS are randomly injected into body tissues they are likely to form teratomas, ugly encapsulated structures of varied body tissues including lung, heart, liver or brain tissue, or bone, teeth or hair.  Careful attention has to be paid to signaling structure to assure the ES or iPS make the kind of tissues desired and only that kind.  This is a fundamental issue of organ regeneration via stem cell therapy whether ES or iPS cells are used.  Also I am unclear about another important matter.  What happens to the telomeres in a cell from a mature person when it is converted to an iPS cell?  Do the telomeres stay short reflecting the age of the donor or are they somehow enlongated as they would be in an ES cell?  Does an iPS cell have sufficient expression of telomerase when it differentiates to carry it through the large number of generations required for effective organ renewal?  As far as I know, these are issues still to be researched.

In terms of aging, the four proteins seem to turn the clock back in a cell to ground zero.  That is, all the epigenetic information (DNA methylation) that cell and its parents, grandparents, great-grandparents, etc.  gathered in the process of many rounds of cell differentiation and division and life experience is completely wiped away in the process of it becoming reprogrammed as an iPS cell.  For halting or even reversing human aging we don’t want that to happen to most of the cells in our body; it would turn us into blobs of undifferentiated stem cells.  What we might like, however, is selectively to erase epigenetic information related to programmed aging while retaining epigenetic information related to cell differentiation.  Or, more simply put, we would like selectively to reset our cells to a younger state while keeping the degree of cell differentiation appropriate to that younger state.  See the discussion of the Programmed genetic changes theory of aging in my Anti-Aging Firewalls treatise.  This is a challenge of a quite different order of magnitude than is simple rebooting. 

We can probably expect important new research results related to iPS cells in the coming year, months or even weeks. 

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