Multi-omic rejuvenation of human cells by maturation phase transient reprogramming.
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Authors
Publication Date
2022-04-08Journal Title
Elife
ISSN
2050-084X
Publisher
eLife Sciences Publications, Ltd
Volume
11
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Gill, D., Parry, A., Santos, F., Okkenhaug, H., Todd, C. D., Hernando-Herraez, I., Stubbs, T. M., et al. (2022). Multi-omic rejuvenation of human cells by maturation phase transient reprogramming.. Elife, 11 https://doi.org/10.7554/eLife.71624
Description
Funder: Milky Way Research Foundation
Funder: Biotechnology and Biological Sciences Research Council
Abstract
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. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of somatic cell reprogramming, which suggests full 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reprogramming" (MPTR) method, where reprogramming factors are selectively expressed until this rejuvenation point then withdrawn. Applying MPTR to dermal fibroblasts from middle-aged donors, we found that cells temporarily lose and then reacquire their fibroblast identity, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. 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 was rejuvenated to a similar extent, including H3K9me3 levels and the DNA methylation ageing clock. The magnitude of rejuvenation instigated by MPTR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.
Keywords
Human, Genetics, Transcription, Ageing, DNA methylation, Rejuvenation, Genomics, Reprogramming, Stem Cells, Regenerative Medicine, Fibroblasts, Humans, DNA Methylation, Middle Aged, Induced Pluripotent Stem Cells, Epigenomics, Cellular Reprogramming, Epigenome
Sponsorship
Wellcome Trust (215912/Z/19/Z)
Wellcome Investigator award (210754/Z/18/Z)
Identifiers
35390271, PMC9023058
External DOI: https://doi.org/10.7554/eLife.71624
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336968
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