Rejuvenating cells through specialized reprogramming and redifferentiation.
Since old non-senescent cells can be reprogrammed to a pluripotent rejuvenated state, which resets the transient loss of regulatory information that accompanies aging in differentiated cells, there is good reason to believe that cells can be directly rejuvenated by reprogramming methods (Rando and Chang, 2012). The key question is how to achieve a reset of cell state that accompanies pluripotency reprogramming without actually creating pluripotent stem cells, which are unstable and capable of tumor formation. Direct transdifferentation to new cell fates, including neurons, skeletal and cardiac muscle has been engineered using specific combinations of forced transcription factors and culture supplements. But how many aging related changes are reset by transdifferentiation and how many require additional resetting?
Recent work from Fred Gage’s lab (Mertens et al., 2015) demonstrates that fibroblasts directly transdifferentiated to neurons largely express the normal neural transcriptome, but retain some age-associated deficits. For example nuclear cytoplasmic transport retains an old dysfunctional phenotype due to decreased expression of Nuclear transport receptor RanBP17. Ectopic RanBP17 further rejuvenates the transdifferentiated neurons, but additional changes are needed to create young neurons equivalent to those that can be derived from first reprogramming to induced pluripotent stem cell state and then differentiation them into neurons. Clearly transdifferentiation per se is not sufficient to completely rejuvenate cells. But this experimental approach allows serial discovery of the factors necessary to achieve complete rejuvenation. Interestingly, expression of progerin, a mutant lamin A/C associated with Hutchinson Gilford Progeria Syndrome, creates similar epigenetic signatures to natural changes in cells from old people.
There are at least two possible routes to achieve rejuvenation via reprogramming: 1) creating multipotent adult stem cells, perhaps even pluripotent stem cells, that can replace old cells that meet a threshold of dysfunction or 2) directly rejuvenating candidate cells, which do not contain oncomutations or are committed to senescence, via reprogramming to a transdifferentiated or redifferentiated state and concomitantly resetting key age-associated epigenetic/epigenomic changes. At RSI, we are elucidating the changes necessary to completely rejuvenate cells via transdifferentiation.
References: Mertens J, Paquola AC, Ku M, Hatch E, Böhnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR, Gonçalves JT, Toda T, Kim Y, Winkler J, Yao J, Hetzer MW, Gage FH. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Cell Stem Cell. 2015 pii: S1934-5909(15)00408-7. Rando TA, Chang HY. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell. 2012 148(1-2):46-57.