Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.

Cellular senescence is a complex cell state with roles in tumor suppression, embryonic development and wound repair. However, when misregulated, senescence contributes to aging and disease. Here we identify that senescent cells generate/break off large membrane-bound fragments of themselves through cell-to-cell adhesion. We designate these as senescent-cell adhesion fragments (SCAFs) which were present in all types of senescent cell examined. We show they contain many organelles from the original cell, but without nuclear material. Quantitative and dynamic profiling shows that SCAFs are large, may persist for a number of days, but rupture and release their contents onto neighboring cells. Protein profiling identifies that SCAFs contain a complex proteome including immune recruitment factors and damage-associated molecular patterns (DAMPs). Functional studies reveal that SCAFs activate signatures related to wound healing and cancer, and promote invasion and migration. Altogether, we uncover an additional cellular feature of senescent cells, by which they deposit intracellular contents on other cells. We speculate this may aid in boosting immune responses, but in chronic situations, may contribute to debris buildup, inflammaging and age-associated changes.