In vivo reprogramming is a promising approach for tissue regeneration in response to injury. Several examples of in vivo reprogramming have been reported in a variety of lineages, but some including skeletal muscle have so far proven refractory. Here, we show that acute and chronic injury enables transcription-factor-mediated reprogramming in skeletal muscle. Lineage tracing indicates that this response frequently originates from Pax7+ muscle stem cells. Injury is associated with accumulation of senescent cells, and advanced aging or local irradiation further enhanced in vivo reprogramming, while selective elimination of senescent cells reduced reprogramming efficiency. The effect of senescence appears to be, at least in part, due to the release of interleukin 6 (IL-6), suggesting a potential link with the senescence-associated secretory phenotype. Collectively, our findings highlight a beneficial paracrine effect of injury-induced senescence on cellular plasticity, which will be important for devising strategies for reprogramming-based tissue repair.
Graphical Abstract Highlights d SUMO acts on chromatin to maintain cellular identity d SUMO impairs somatic enhancer inactivation early during iPSC reprogramming d Loss of SUMO converts ESCs into a 2C-like state by releasing PRC1.6 from the Dux locus d Loss of SUMO in ESCs leads to genome-wide loss of H3K9me3-dependent heterochromatin
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