Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
- Babraham Institute, United Kingdom
- Chronomics Limited, United Kingdom
- Instituto Gulbenkian de Ciência, Portugal
- Altos Labs, United Kingdom
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. 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 temporarily lose and then reacquire their fibroblast identity during MPTR, 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, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR 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 more extensive reprogramming does not necessarily result in greater rejuvenation but instead 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.
Data availability
DNA methylation array and RNA-seq data are available on Gene Expression Omnibus under the accession number: GSE165180.
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Multi-omic rejuvenation of human cells by maturation phase transient reprogrammingNCBI Gene Expression Omnibus, GSE165180.
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Predicting age from the transcriptome of human dermal fibroblastsGene Expression Omnibus, GSE113957.
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Impact of regulatory variation across human iPSCs and differentiated cells [RNA-seq]Gene Expression Omnibus, GSE107654.
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Impact of regulatory variation across human iPSCs and differentiated cells [methylation]Gene Expression Omnibus, GSE110544.
Article and author information
Author details
Funding
Biotechnology and Biological Sciences Research Council
- Diljeet Gill
- Fátima Santos
- Hanneke Okkenhaug
- Christopher D Todd
- Irene Hernando-Herraez
- Thomas M Stubbs
- Inês Milagre
- Wolf Reik
Wellcome Trust
- Aled Parry
Milky Way Research Foundation
- Diljeet Gill
- Wolf Reik
Wellcome Investigator award (210754/Z/18/Z)
- Wolf Reik
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jessica K Tyler, Weill Cornell Medicine, United States
Publication history
- Preprint posted: January 17, 2021 (view preprint)
- Received: June 24, 2021
- Accepted: April 6, 2022
- Accepted Manuscript published: April 8, 2022 (version 1)
- Version of Record published: April 21, 2022 (version 2)
Copyright
© 2022, Gill et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
eLife 11:e71624.
https://doi.org/10.7554/eLife.71624
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