A new study outlines multiple ways in which epiblast stem cells can be reprogrammed back into a fully pluripotent state, paving the way for a better understanding of epigenetics.
The role of epigenetics
Epigenetics are why our cells, which all have the same DNA, differ in function. A bone cell has the same genetics as a nerve cell, but its epigenetic switches instruct it to perform the functions of a bone cell and not a nerve cell. Epigenetic alterations, however, are one of the primary hallmarks of aging. As we age, harmful epigenetic switches are activated and beneficial ones are deactivated, causing age-related dysfunction. This may even lead to inflammation, which causes further epigenetic damage, leading to a dangerous feedback loop.
An in-depth study
This study outlined multiple routes that stem cells can take towards becoming fully pluripotent; this is the reverse of normal development, in which a fully pluripotent embryo ultimately differentiates itself into the cell types that make up the older organism. Multiple signaling drivers were used, and while each of these drivers had different effects, taking different routes towards a fully pluripotent state, their destination was the same, leading the researchers to label naive pluripotency as an ‘attractor’.
Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning and end states are questions of wide interest. Here we show that acquisition of naive pluripotency can follow transcriptionally and mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to naive pluripotency induction, whereas another transiently resembles the early inner cell mass and correspondingly gains greater developmental potency. These routes utilize distinct signaling networks and transcription factors but subsequently converge on the same naive endpoint, showing surprising flexibility in mechanisms underlying identity transitions and suggesting that naive pluripotency is a multidimensional attractor state. These route differences are reconciled by precise expression of Oct4 as a unifying, essential, and sufficient feature. We propose that fine-tuned regulation of this “transition factor” underpins multidimensional access to naive pluripotency, offering a conceptual framework for understanding cell identity transitions.
Unwanted but useful
Obviously, naive pluripotency is not something we want to happen to our existing cells, even our stem cells; if our cells forgot what they were supposed to be, they could easily grow into the incorrect cell types for the organs in which they are located, such as bone cells in the heart or brain.
This is exactly what makes this study useful for life extension researchers, however. By describing the ways in which cells are attracted towards this naive, fully pluripotent state, and the routes they take to get there, this study offers a new perspective for researchers who wish to use Oct4 and related signals to induce a partial epigenetic reset, the goal of which is to restore the epigenetics of adult cells to a state that is fully functional yet unmarred by harmful epigenetic alterations.
As the study makes clear, precise Oct4 expression is “unifying, essential, and sufficient” to ultimately induce naive pluripotency in epiblast stem cells. This critical fact, and the related research on the signaling methods that determine cell fate, may possibly offer new insight for researchers working on Oct4-, OSKM-, and OSKMLN-based therapies that aim to cure us of one of the principal hallmarks of aging.