Senescent cells communicate via intercellular protein transfer

Abstract

Mammalian cells mostly rely on extracellular molecules to transfer signals to other cells. However, in stress conditions, more robust mechanisms might be necessary to facilitate cell-cell communications. Cellular senescence, a stress response associated with permanent exit from the cell cycle and the development of an immunogenic phenotype, limits both tumorigenesis and tissue damage. Paradoxically, the long-term presence of senescent cells can promote tissue damage and aging within their microenvironment. Soluble factors secreted from senescent cells mediate some of these cell-nonautonomous effects. However, it is unknown whether senescent cells impact neighboring cells by other mechanisms. Here we show that senescent cells directly transfer proteins to neighboring cells and that this process facilitates immune surveillance of senescent cells by natural killer (NK) cells. We found that transfer of proteins to NK and T cells is increased in the murine preneoplastic pancreas, a site where senescent cells are present in vivo. Proteomic analysis and functional studies of the transferred proteins revealed that the transfer is strictly dependent on cell-cell contact and CDC42-regulated actin polymerization and is mediated at least partially by cytoplasmic bridges. These findings reveal a novel mode of intercellular communication by which senescent cells regulate their immune surveillance and might impact tumorigenesis and tissue aging.

Animal and human models to understand ageing

“…It was by studying cell senescence in vitro that the SASP was identified [92], and the ability of senescent cells to induce senescence in surrounding cells [93], both through secreted SASP factors and potentially through direct cell-cell contacts [94].…”

Senescent cells talk frankly with their neighbors

“…2 CBs, which in some conditions are called tunneling nano- tubes, are open on both edges and allow transfer of cytoplasmic content to neighboring cells. Interestingly, we also identified mitochondria and lysosomes in CBs, implying that organelles might be transferred between the cells.…”

“…4,6 We have recently demonstrated that in addition to secretion, senescent cells affect neighboring cells by direct intercellular protein transfer (IPT). 2 Proteins from senescent cells are directly transferred to recipient neighboring cells, such as immune and cancer cells, triggering activation of signaling pathways in these cells, ultimately leading to changes in cellular behavior.…”

“…In all these places senescent cells communicate with cells in their surroundings and modulate the function of these cells. [2][3][4][5] The effect of senescent cells on nearby cells is commonly attributed to the secretion of cytokines, chemokines and matrix metalloproteinases. 4,6 We have recently demonstrated that in addition to secretion, senescent cells affect neighboring cells by direct intercellular protein transfer (IPT).…”

Senescent cell death brings hopes to life

“…These cells secrete a plethora of pro-inflammatory factors that might aid their removal by the immune system. [1][2][3] However, at advanced age senescent cells gradually accumulate in tissues and the secretory phenotype promotes a chronic "sterile" inflammation which is a hallmark of unhealthy aging. Elimination of senescent cells in mice by a genetic approach led to a decreased burden of age-related disorders, and an increased median survival of the mice.…”