Further Investigations of Partial, Transient Cellular Reprogramming

Reprogramming cells from old tissues into induced pluripotent stem cells has the effect of reversing many of the epigenetic changes that are characteristic of age, thus restoring mitochondrial function and other aspect of cell behavior. This is a limited rejuvenation: it can't do much about DNA damage, and nor can it make cells clear persistent molecular waste that even youthful cells struggle with. Nonetheless, applying reprogramming to living mice has produced benefits to health, suggesting that if the process can be sufficiently controlled, then it may be a useful basis for therapy - perhaps globally forcing cells to behave more as though they are in young tissues. Groups such as Turn.bio are investigating the use of partial and transient reprogramming, in search of a balance point at which cells are rejuvenated without losing their cell type or radically changing their behavior. Here, another groups reports on early results from their analogous efforts to develop a methodology of safe transient reprogramming.

Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells.

Here we have developed the first "maturation phase transient reprogramming" (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells reacquire their fibroblast identity following MPTR, possibly as a result of persisting epigenetic memory at enhancers. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent.

The magnitude of rejuvenation instigated by MTPR is substantially greater than that achieved in previous transient reprogramming protocols. MPTR fibroblasts produced youthful levels of collagen proteins, suggesting functional rejuvenation. Overall, our work demonstrates that it is possible to separate rejuvenation from pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

Link: https://doi.org/10.1101/2021.01.15.426786

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