As many of you well know, the U.S. presidential election recently came to a close. Over the last year, there have been numerous speeches from a variety of sources, some of which have been able to rally the masses, due not only to their content but also the speaker’s masterful elocution. Indeed, when it comes to reversing our pre-formed opinions, how a message is delivered clearly plays a significant role.
Curiously, the same seems to hold true for cellular reprogramming.
When Dr. Shinya Yamanaka developed induced pluripotent stem cell (iPSC) technology in 2007, he showed that the introduction of a cassette of genes (Oct 4, Klf4, Sox2, c-Myc) could revert adult cells back to a pluripotent state. In these experiments, viruses were used as a gene delivery mechanism. However, concern that viruses could dysregulate host genes (essentially, the possibility that the viruses may cause the target cells to respond and change in unintended, and perhaps harmful ways) subsequently led to a flurry of research towards non-viral methods of gene delivery, for example, by using cell permeant peptides (CPP), in which a terminal peptide sequence enables DNA to pass through the cell membrane. Interestingly, the efficiency of CPPs at creating iPS cells is substantially lower than when viruses are used, a finding that caused researchers at Stanford University to pause and ask – could it be something intrinsic to the viruses that contributed to better reprogramming?
The answer, they found, was yes.
In the Oct 26 issue of Cell, Lee et al. show that CPPs are normally slower and less efficient than viral vectors at cellular reprogramming but that this difference is eliminated if the gene-carrying CPPs are used in conjunction with an “empty” viral vector that simply carries a fluorescence reporter gene. It seems that the viruses act to sort of “loosen up” the cells for the pluripotency genes’ messages. And I mean literally. By activating the inflammatory response through TLR3 receptors, the viruses cause epigenetic changes that put chromatin in a more open state that is conducive to iPSC formation.
Importantly, the investigators showed that this response can be mimicked using synthetic TLR3 agonists (poly I:C) and that these can increase the efficiency of CPP mediated iPSC formation. Thus, they’ve shown a more efficient means of iPSC production without the risks associated with using viral vectors!
What I find particularly delightful about this paper is that it brings to light a previously overlooked contributor to iPSC formation and opens many additional avenues for exploration. Can activation of different receptors yield similar responses? Can knowledge of this pathway help us in our attempts to coax cells towards different fates? If the late ‘90s/early 2000’s were the years of genetics, we are now in the era of epigenetics, where it is important to get into the minds of cells to convince them to express genes that will give us clinically relevant cell phenotypes. Thanks to Lee et al., we now know that induction of the inflammatory cascade may be a critical method to bringing cells on board with our vision for their future.
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