Senescent Cells Promote Senescence in Other Cells in Part via Small Extracellular Vesicle Secretion
It is by now well established that senescent cells promote senescence in neighboring cells. This is a useful and necessary part of the benefits of the transient presence of senescent cells in the contexts of cancer suppression and coordination of wound healing. But when senescent cell clearance falters in later life, and senescent cells begin to linger and accumulate, this promotion of further senescence makes matters worse. One of the ways in which senescent cells promote senescence is via relatively well mapped and well understood inflammatory signaling. Here, however, researchers note that there are other pathways involved, in which the signaling involves the contents of small extracellular vesicles. Interfering in senescent cell signaling as a basis for therapy is likely a more challenging path forward than selective destruction of senescent cells, but efforts are being made in both directions regardless.
Senescent cells accumulate during both physiological and pathological processes, including aging. They are characterized by the expression of the cell cycle inhibitor p16INK4A and the senescence-associated secretory phenotype (SASP). However, fibroblasts ectopically expressing p16INK4A do not exhibit a canonical SASP, leaving the mechanisms by which they communicate with their microenvironment largely unknown. Here, we show that human primary fibroblasts ectopically expressing p16INK4A release significantly more small extracellular vesicles (sEVs) than proliferating cells. Furthermore, we demonstrate that sEVs isolated from p16INK4A-expressing fibroblasts are biologically active and can mediate paracrine senescence in proliferating cells.
Specifically, treatment with these sEVs induces proliferative arrest, upregulates p16INK4A expression, and activates a DNA damage response in recipient cells. Notably, sEVs from p16INK4A-expressing cells do not induce the expression of the canonical SASP factors IL-6 and IL-8, suggesting that they promote senescence independently of a classical inflammatory response. We further demonstrate sEV-mediated transmission of paracrine senescence in two cellular models of aging: progerin expression and telomere dysfunction induced by a dominant-negative telomere mutant. In addition, sEVs isolated from fibroblasts derived from aged donors induce paracrine senescence in fibroblasts from young donors. Collectively, these findings identify sEVs released by senescent and aged cells as an important mechanism of intercellular communication and a key mediator of paracrine senescence.