Extracellular Vesicles as New Players in Cellular Senescence

Urbanelli, Lorena; Buratta, Sandra; Sagini, Krizia; Tancini, Brunella; Emiliani, Carla

doi:10.3390/ijms17091408

Cited by 97 publications

(91 citation statements)

References 92 publications

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Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 99%

“…A large body of evidence shows that EVs, including exosomes and microvesicles, that are important mediators of intercellular communication, represent a key component of SASP. 54,55 In general, EVs carry and transfer a wide variety of molecules, such as micro RNAs (miRNAs), messenger RNAs, DNA, and proteins. Remarkably, EVs secreted from senescent cells have unique characteristics and contribute to regulate the behavior of recipient cells similarly to soluble SASP factors.…”

Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 99%

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Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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NK cells are lymphocytes of the innate immune system, which are able to deal promptly with stressed cells. Cellular senescence is a cell stress response leading to cell cycle arrest that plays a key role during tissue homeostasis and carcinogenesis. In this review, how senescent cells trigger an immune response and, in particular, the ability of NK cells to recognize and clear senescent cells are discussed. Special attention is given to the NK cell‐mediated clearance of senescent tumor cells. NK cells kill senescent cells through a mechanism involving perforin‐ and granzyme‐containing granule exocytosis, and produce IFN‐γ following senescent cell interaction, leading to hypothesize that NK cell‐mediated immune clearance of senescent cells not only relies on direct killing but also on cytokine production, that in turn can promote macrophage activation. These aspects, as well as the ability of the senescence‐associated secretory phenotype and senescent cell‐produced extracellular vesicles to modulate NK cell effector functions, are described.

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Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 99%

Section: Evs As a Key Component Of Sasp Modulate Nk Cell Functionsmentioning

confidence: 99%

Senescent cells: Living or dying is a matter of NK cells

Antonangeli

Zingoni

Soriani

et al. 2019

Journal of Leukocyte Biology

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“…Senescence is a complex cellular program induced by genotoxic, replicative, or oncogenic stress, in which cell-cyclearrested cells remain metabolically active and secrete several soluble factors, also known as the "senescence-associated secretory phenotype" (SASP), which mediates a variety of cellular responses, including modulation of cancer immune surveillance. Studies have shed a new light on the role of exosomes in mediating the cell-to-cell transmission of senescence signals, suggesting that exosomes may act as new components of the SASP (22).…”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 Trans-Presentation

Borrelli

Ricci²,

Vulpis

et al. 2018

Cancer Immunology Research

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Treatment of multiple myeloma (MM) cells with sublethal doses of genotoxic drugs leads to senescence and results in increased NK cell recognition and effector functions. Herein, we demonstrated that doxorubicin- and melphalan-treated senescent cells display increased expression of IL15, a cytokine involved in NK cell activation, proliferation, and maturation. IL15 upregulation was evident at the mRNA and protein level, both in MM cell lines and malignant plasma cells from patients' bone marrow (BM) aspirates. However, IL15 was detectable as a soluble cytokine only , thus indicating a functional role of IL15 in the BM tumor microenvironment. The increased IL15 was accompanied by enhanced expression of the IL15/IL15RA complex on the membrane of senescent myeloma cells, allowing the functional trans-presentation of this cytokine to neighboring NK cells, which consequently underwent activation and proliferation. We demonstrated that MM cell-derived exosomes, the release of which was augmented by melphalan treatment in senescent cells, also expressed IL15RA and IL15, and their interaction with NK cells in the presence of exogenous IL15 resulted in increased proliferation. Altogether, our data demonstrated that low doses of chemotherapeutic drugs, by inducing tumor cell senescence and a senescence-associated secretory phenotype, promoted IL15 trans-presentation to NK cells and, in turn, their activation and proliferation, thus enhancing NK cell-tumor immune surveillance and providing new insights for the exploitation of senescence-based cancer therapies..

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“…Moreover, it was demonstrated that the functional hypothalamic stem/ progenitor cells release exosomes into the cerebral spinal fluid that likely contribute to slowing aging through transfer of miRNAs (57). Conversely, it has been demonstrated that senescent cells release more EVs and with a different composition (58)(59)(60), likely contributing to the SASP. Taken together, these results suggest that functional stem/ progenitor cell-derived EVs are able to extend healthspan and lifespan whereas senescent cell-derived EVs could function as pro-geronic factors.…”

Section: Evsmentioning

confidence: 99%

Extracellular vesicles and aging

Robbins¹

2017

Stem Cell Investig.

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AgingIt is estimated that in the next 20 years, the number of individuals in the United States over the age of 65 will double, numbering more than 70 million individuals. Unfortunately, as we age there is an unavoidable and progressive loss of the ability to maintain tissue homeostasis under stress and an attrition of functional reserve. As a consequence, the incidence of numerous debilitating diseases increases nearly exponentially with age, including cardiovascular disease, neurodegeneration, diabetes, osteoarthritis, and osteoporosis. Over 90% of individuals >65 years of age have at least one chronic disease, while >70% have at least two. These chronic diseases account for 75% of our healthcare costs, amounting to approximately $3 trillion in costs last year alone. Indeed, chronic diseases of the elderly are the greatest healthcare burden in the United States and seriously impact the quality of life of a large segment of the population. Thus, there is a significant need to understand mechanisms driving aging and to develop novel therapeutics. Given the diverse roles of blood-borne EVs in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process. This review focuses on the role EVs could play in aging, their therapeutic application for extending healthspan and their potential for use as biomarkers of unhealthy aging. Abstract: Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system. As our world population ages dramatically over the next decades, this will only increase.Hence, there is a great need to discover fundamental mechanisms of aging to enable development of strategies for minimizing the impact of aging on our health and economy. There is general agreement that cell autonomous mechanisms contribute to aging. As cells accrue damage over time, they respond to it by triggering individual cell fate decisions that ultimately disrupt tissue homeostasis and thus increase risk of morbidity. However, there are numerous lines of evidence, including heterochronic parabiosis and plasma transfer, indicating that cell non-autonomous mechanisms are critically important for aging as well. In addition, senescent cells, which accumulate in tissues with age, can display a senescence-associated secretory phenotype (SASP) that contributes to driving aging and loss of tissue homeostasis through a non-cell autonomous mechanism(s). Given the diverse roles of blood-borne extracellular vesicles (EVs) in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process through cell non-autonomous mechanisms. The fact that senescent cells release more EVs and with a different composition suggests they contribute to the adverse effects of senescence on aging. In addition, the ability of EVs from functional progenitor cells to promote tissue regeneration suggests that stem cell-derived EVs could be used therapeutica...

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Extracellular Vesicles as New Players in Cellular Senescence

Cited by 97 publications

References 92 publications

Senescent cells: Living or dying is a matter of NK cells

Senescent cells: Living or dying is a matter of NK cells

Drug-Induced Senescent Multiple Myeloma Cells Elicit NK Cell Proliferation by Direct or Exosome-Mediated IL15 Trans-Presentation

Extracellular vesicles and aging

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