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The accumulation of senescent cells in all tissues throughout the body is one of the causes of aging. These errant cells are never present in enormous numbers relative to non-senescent cells that make up the overwhelming majority of tissues even in very old people. Yet they cause significant harm. Senescent cells secrete a mix of inflammatory signals that disrupts tissue structure and function, and provokes a state of chronic inflammation that further contributes to the progression of age-related disease. Much of this signaling, as for any cell type, is carried via extracellular vesicles, membrane-bound packages of molecules that pass between cells.
In recent years, a great deal of attention has been given to the secretion of vesicles and their effects on recipient cells. One strong motivation for this work is that vesicles they are comparatively easy to harvest and use in comparison to the cells that create them. Many first generation stem cell therapies, those that produce therapeutic effects via signals delivered by the transplanted cells in the short time before they die, might be replaced with delivery of vesicles, which is logistically a much easier form of treatment.
In the case of senescent cells, researchers are investigating secreted vesicles and their contents to better understand exactly how these cells contribute to age-related disease, at the very detailed level of molecular interactions. This work is largely disconnected from efforts to destroy senescent cells via senolytic treatments, however: the development community doesn’t need to understand how senescent cells cause harm in order to prevent them from causing harm. This is an important aspect of much of the present development of rejuvenation therapies, in that the mode of treatment effectively bypasses the lack of scientific knowledge regarding exactly how specific mechanisms of aging progress in detail.
Osteoarthritis (OA) is an age-related and posttraumatic degenerative joint disease that is accompanied by cartilage degradation, persistent pain, and impairment of mobility. Senescent cells (SnCs) are a newly implicated factor in the development of OA. Cellular senescence is characterized by a proliferation arrest, which protects against cancer, as well as other changes that can also contribute to aging phenotypes and pathologies. SnCs accumulate with age in many tissues, including articular cartilage, where they promote pathological age-related deterioration.
These and other tissue pathologies are presumably mediated by the secretion of extracellular proteases, proinflammatory cytokines, chemokines, and growth factors, termed the senescence-associated secretory phenotype (SASP), by SnCs. The local elimination of SnCs in a murine model of posttraumatic OA (PTOA) reduced pain and increased cartilage development. Bridging these results to human cells, the selective removal of senescent chondrocytes improved the cartilage-forming ability of chondrocytes isolated from human arthritic tissue. Recent findings suggest that SnCs can transmit limited senescent phenotypes to nearby cells, termed secondary or paracrine senescence. Understanding the mechanisms of this SnC transmission may inform mechanisms of OA disease causation.
Extracellular vesicles (EVs), including exosomes and microvesicles, are small membrane-limited particles that can participate in intercellular communication. EVs mediate local tissue development and homeostasis through the transfer of cargoes, such as proteins and microRNAs (miRs). For example, the EVs present in articular cartilage and synovial fluid can contribute to mineralization of the cartilage extracellular matrix (ECM) and formation of an inflammatory joint environment. Recently, it was reported that SnCs secrete more EVs compared with their nonsenescent counterparts. These senescent-associated EVs may also induce senescence in neighboring cells. In the case of arthritis, SnCs can modulate the environment of the articular joint, increasing inflammation and ECM degradation. It is not known whether EVs secreted by SnCs in the articular joint are responsible for the progression of OA or whether they can be use as indicators of disease progression and treatment efficacy.
In this study, we found that senescent chondrocytes isolated from OA patients secrete more EVs compared with nonsenescent chondrocytes. These EVs inhibit cartilage ECM deposition by healthy chondrocytes and can induce a senescent state in nearby cells. We profiled the miR and protein content of EVs isolated from the synovial fluid of OA joints from mice with SnCs. After treatment with a molecule to remove SnCs, termed a senolytic, the composition of EV-associated miR and protein was markedly altered. The senolytic reduced OA development and enhanced chondrogenesis, and these were attributable to several specific differentially expressed miRs (miR-30c, miR-92a, miR-34a, miR-24, miR-125a, miR-150, miR-186, and miR-223) and proteins (Serpina and aggrecan). In aged animals, treatment with senolytic modulated the inflammatory response by decreasing recruitment and activation of myeloid and phagocytic cells. Collectively, these findings suggest that altered levels of synovial EV miRs and proteins are a potential mechanism by which SnCs can transfer senescence, inhibit tissue formation, and promote OA development. When isolated from synovial fluid, EVs may also be used to predict therapeutic response to senolytic therapies in the articular joint.