Senescence-messaging secretome factors trigger premature senescence in human endometrium-derived stem cells

Vassilieva, Irina O.; Reshetnikova, Galina; Shatrova, A. N.; Tsupkina, Nataliya V.; Kharchenko, M. V.; Алексеенко, Л. Л.; Nikolsky, Nikolay; Burova, Elena

doi:10.1016/j.bbrc.2018.01.163

Cited by 24 publications

(23 citation statements)

References 25 publications

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“…Senescent cells express numerous SASP factors, including proteases, cytokines, chemokines and matrix metalloproteinases (MMPs, 12 , 14 , 39 – 41 ), which could mediate CIPN. Therefore, we measured SASP factors in DRG from mice treated with cisplatin.…”

Section: Resultsmentioning

confidence: 99%

Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice

Acklin

Zhang

et al. 2020

Sci Rep

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Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16 INK4A and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological 'senolytic' agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN. Chemotherapy-induced peripheral neuropathy, a common dose-limiting toxicity of many chemotherapy regimens, limits the potentially curative effects of systemic chemotherapy 1-4. Particularly, platinum-based chemotherapeutics, such as cisplatin, are known to cause systemic neuronal toxicity. Clinically, cisplatin-induced peripheral neuropathy (CIPN) presents as burning, shooting or electric-shock-like pain affecting the feet and hands 2,5 , for which no effective treatments or preventive measures are available 2-4,6. Cisplatin's antineoplastic effects are achieved through the formation of platination products in nuclear DNA 7-9. These DNA-base crosslinks distort DNA helices, interrupting replication and transcription, eventually inducing cell cycle arrest, senescence, or cell death 7-10 .While these effects of cisplatin on cancer cells is desired for treatment, the same processes in normal tissue can cause toxicity. An important senescence phenotype, termed therapy-induced senescence (TIS), can be induced by DNA damage-based chemotherapeutics. The genotoxic stress caused by these agents induces senescence during cancer treatment and has been shown to promote the adverse effects of chemotherapy 11,12. Cellular senescence, a

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Section: Resultsmentioning

confidence: 99%

Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice

Acklin

Zhang

et al. 2020

Sci Rep

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“…Due to the secretion of SASP-related proteins (including pro-inflammatory cytokines, chemokines, growth factors and proteases), senescent cells can promote chronic inflammation and change the microenvironment of tissues and functions of adjacent cells, leading to increased susceptibility for skin disorders [ 18 , 19 ]. The senescence progression is accompanied with enhanced ROS level and activation of histone H2A.X [ 20 ]. Human-induced pluripotent stem cells-EVs promoted cell proliferation, decreased cellular ROS levels and production of γ-H2A.X and SASP, and thus alleviated senescence [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Plasma endothelial cells-derived extracellular vesicles promote wound healing in diabetes through YAP and the PI3K/Akt/mTOR pathway

Wei

Wang

et al. 2020

Aging

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Extracellular vesicles are involved in skin wound healing and diabetes. After enrichment and identification, plasma endothelial cells-derived-extracellular vesicles were cocultured with skin fibroblasts or HaCaT. The gainand loss-of functions were performed to measure fibroblast proliferation, senescence, and reactive oxygen species. Levels of senescence-related proteins, senescence-associated secretory phenotypes, vascular markers, YAP and the PI3K/Akt/mTOR pathway-related proteins were determined. Diabetic mice were induced to establish skin wound model. After endothelial cells-derived-extracellular vesicles were injected into skin wound modeling mice, skin wound healing was evaluated. Endothelial cells-derived-extracellular vesicles treatment enhanced fibroblast proliferation, and decreased senescence through the elevation of YAP nuclear translocation and activation the PI3K/Akt/mTOR pathway. YAP inhibition reversed the effect of plasma endothelial cells-derived-extracellular vesicles on fibroblast proliferation. Endothelial cells-derived-extracellular vesicles also promoted wound healing in diabetic mice, increased microvascular density, collagen deposition, macrophage infiltration and positive rates of vascular markers, and inhibited YAP phosphorylation and senescence. Plasma endothelial cells-derived-extracellular vesicles prevent fibroblast senescence and accelerate skin wound healing in diabetic mice by reducing YAP phosphorylation and activating the PI3K/Akt/mTOR pathway. This study may provide novel insights for skin disorders in diabetic mice.

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“…For example, it was recently demonstrated that the conditioned medium (CM) from Senescent MSCs triggered deceleration of cell proliferation and induced a senescent phenotype of normal MSCs. The senescence inducing pathway appeared to be transmitted through p53/p21/Rb and p16/MAPKAPK-2/Rb signaling [26]. Ritschka et al believed that the effect of SnCs on cell proliferation was also bidirectional [7].…”

Section: Discussionmentioning

confidence: 99%

Intraarticular senescent chondrocytes impair the cartilage regeneration capacity of mesenchymal stem cells

et al. 2019

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BackgroundSenescent cells exert a significant influence over their surrounding cellular environment. Senescent chondrocytes (SnChos) were found to be accumulated in degenerated cartilage present in joints affected by osteoarthritis. The influence of SnChos on exogenously transplanted stem cells has yet to be reported.MethodsIn this study, we evaluated the interactions between SnChos and bone marrow mesenchymal stem cells (BMSCs) when co-cultured as well as in the intra-articular senescent microenvironment (IASM). The effect of IASM on cartilage regeneration was also assessed.ResultsIt was found that a small fraction of SnChos induced BMSC cellular senescence and apoptosis. SnChos also inhibited proliferation, facilitated stemness, and suppressed chondrogenic differentiation of BMSCs. BMSCs induced the apoptosis of SnChos, reduced the proportion of SnChos, stimulated SnChos proliferation, and revealed a bidirectional effect on SnChos inflammaging. IASM significantly suppressed the survival, proliferation, and appropriate differentiation of grafted BMSCs in vivo, all of which impaired cartilage regeneration. Anti-senescence agent ABT-263 was able to partly rescue the cells from the negative effects of SnChos.ConclusionsThe SnChos and BMSCs interacted with each other at cellular senescence, apoptosis, proliferation, differentiation, and cell functions. This interaction impaired the cartilage repair of MSCs. Anti-senescence agent provided a possible solution for this impairment.Electronic supplementary materialThe online version of this article (10.1186/s13287-019-1193-1) contains supplementary material, which is available to authorized users.

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Senescence-messaging secretome factors trigger premature senescence in human endometrium-derived stem cells

Cited by 24 publications

References 25 publications

Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice

Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice

Plasma endothelial cells-derived extracellular vesicles promote wound healing in diabetes through YAP and the PI3K/Akt/mTOR pathway

Intraarticular senescent chondrocytes impair the cartilage regeneration capacity of mesenchymal stem cells

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