Amphiregulin mediates non-cell-autonomous effect of senescence on reprogramming

Cellular senescence is an irreversible growth arrest with a highly dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence has been implicated in somatic reprogramming to pluripotency. The cell-intrinsic proliferation arrest is a barrier for reprogramming, whereas the SASP facilitates the cell fate conversion in nonsenescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we have further investigated how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. We identified a catalog of SASP factors and pathways potentially involved in the cell fate conversion using an unbiased proteomic analysis. Amphiregulin (AREG), a growth factor frequently secreted by the senescent cells, promotes in vitro reprogramming by accelerating proliferation and MET via the EGFR signaling pathway. Of note, AREG treatment diminished the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in the skeletal muscle. Hence, senescence could facilitate cellular plasticity via various SASP factors to promote reprogramming and tissue repair.