Multi-omic rejuvenation of human cells by maturation phase transient reprogramming
"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
Previous attempts at
transient reprogramming have been restricted to the initiation phase in order to conserve
initial cell identity (Lu et al., 2020; Ocampo et al., 2016; Sarkar et al., 2020). This is a valid
concern as fully reprogrammed iPSCs can be difficult to differentiate into mature adult cells
and instead these differentiated cells often resemble their foetal counterparts (Hrvatin et
al., 2014). With our approach, cells temporarily lose their cell identity as they enter the
maturation phase but, importantly, reacquire their initial somatic fate when the
reprogramming factors are withdrawn. This may be the result of persisting epigenetic
memory at enhancers (Jadhav et al., 2019), which notably we find is not erased until the
stabilisation phase. With our method employing longer periods of reprogramming, we
observed robust and substantial rejuvenation of the whole transcriptome as well as aspects
of the epigenome, with many features becoming approximately 30 years younger. This
extent of rejuvenation is substantially greater than what has been observed previously for
transient reprogramming approaches that reprogram within the initiation phase. The
methylome appears to require longer reprogramming to substantially rejuvenate and
consequently, previous work using shorter lengths of reprogramming has resulted in
modest amounts of rejuvenation of the methylome (Lu et al., 2020; Sarkar et al., 2020).
Edited by Iporuru, 18 January 2021 - 07:24 AM.
