Cambridge University researchers use iPS technology to make skin cells 30 years younger!

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Cambridge University researchers use iPS technology to make skin cells 30 years younger!

Aging is the gradual decline in an organism’s fitness that occurs over time, leading to tissue dysfunction and disease.

At the cellular level, aging is associated with decreased function, altered gene expression, and epigenome disturbances.

Somatic cell reprogramming, the process of converting somatic cells into induced pluripotent stem cells (iPSCs), can reverse these age-related changes.

However, during iPSC reprogramming, somatic identity is lost and can be difficult to regain because redifferentiated iPSCs often resemble fetal rather than mature adult cells.

On April 8, 2022, Diljeet Gill et al. of the University of Cambridge published a research paper titled ” Multi-omic rejuvenation of human cells by maturation phase transient reprogramming ” online in eLife , which developed the first ” maturation phase transient reprogramming”. programming” (MPTR) approach, in which reprogramming factors are expressed prior to this regeneration point and their induction is then withdrawn.

Using dermal fibroblasts from middle-aged donors, the study found that cells temporarily lost and then regained their fibroblast identity during MPTR, possibly due to epigenetic memory of enhancers and/or some fibroblasts Sustained expression of genes.

Excitingly, the study’s approach greatly restored multiple cellular properties, including the transcriptome , which was restored to about 30 years old, according to a new transcriptome clock measurement.

The epigenome, including H3K9me3 histone methylation levels and the DNA methylation senescence clock, was rejuvenated to a similar extent. In addition, MPTR fibroblasts produced youthful levels of collagen and showed partial functional recovery of their migration speed.

Finally, this work shows that more extensive reprogramming does not necessarily lead to greater rejuvenation, but rather that there is an optimal time window for rejuvenating the transcriptome and epigenome.

Overall, the study demonstrates that it is possible to separate rejuvenation from full pluripotency reprogramming, which will lead to the discovery of new antiaging genes and therapies.

Cambridge University researchers use iPS technology to make skin cells 30 years younger!

Senescence is the gradual decline of cellular and tissue function over time in nearly all organisms and is associated with multiple molecular hallmarks such as telomere shortening, genetic instability, epigenetic and transcriptional changes, and the accumulation of misfolded proteins.

This leads to disturbed nutrient sensing, increased incidence of mitochondrial dysfunction and cellular senescence, which affects overall cellular function, intercellular communication, promotes stem cell pool depletion, and contributes to tissue dysfunction.

The progression of some aging-related changes, such as transcriptomic and epigenetic changes, can be measured with high accuracy, so they can be used to construct an “aging clock” that predicts chronological age in humans and other mammals with high precision.

Since transcriptomic and epigenetic changes are reversible, this raises the intriguing question of whether the molecular properties of aging can be reversed and cellular phenotypes restored.

Cambridge University researchers use iPS technology to make skin cells 30 years younger!

Transiently reprogrammed cells regain their original cellular identity (image via eLife )

Induced pluripotent stem cell (iPSC) reprogramming is a process by which virtually any somatic cell can be transformed into an embryonic stem cell-like state.

Interestingly, iPSC reprogramming reversed many age-related changes, including telomere shortening and oxidative stress.

Notably, the epigenetic clock was reset to 0, suggesting that reprogramming can reverse the epigenetic changes associated with aging.

However, iPSC reprogramming also results in the loss of primitive cell identity and thus loss of function.

In contrast, a transient reprogramming approach in which Yamanaka factors (Oct4, Sox2, Klf4, c-Myc) are expressed for a short period of time (~50 days) may enable regeneration without loss of cellular identity.

Reprogramming can be performed in vivo, and in fact periodic expression of Yamanaka factor in vivo extends lifespan and improves cellular function in wild-type mice.

Another approach to in vivo reprogramming also demonstrated reversal of age-related changes in retinal ganglion cells and was able to restore vision in a mouse model of glaucoma.

Recently, transient reprogramming in vitro has been shown to reverse multiple aspects of human fibroblast and chondrocyte aging.

Nonetheless, the epigenetic reversal of senescence achieved by previous transient reprogramming methods was modest (about 3 years) compared to the dramatic reduction achieved by full iPSC reprogramming.

Here, the study established a new transient reprogramming strategy (taking about 13 days) in which Yamanaka factors were expressed during the maturation stage of reprogramming and then abrogated their induction (mature stage transient reprogramming, MPTR ), the study was able to achieve a robust and very significant age reversal (~30 years), while preserving the protocell identity overall.

Reference:

https://elifesciences.org/articles/71624

Cambridge University researchers use iPS technology to make skin cells 30 years younger!

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