Zhulin Xue, Yexiang Jiang, Bowen Meng, Lu Lu, Meng Hao, Yi Zhang, Songtao Shi, Zili Li, Xueli Mao
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SiRNA and chemicals were used for gain and loss-of-function assay. <b>Results:</b> In this study, we show that loss of mechanical force led to cellular apoptotic resistance and aging related phenotype, thus reducing the number of apoVs in the circulation due to down-regulated expression of Piezo1 and reduced calcium influx. And systemic infusion of apoVs was able to rescue Piezo1 expression and calcium influx, thereby, rescuing mechanical unloading-induced cellular apoptotic resistance, senescent cell accumulation. <b>Conclusions:</b> This study identified a previously unknown role of mechanical force in maintaining apoptotic homeostasis and eliminating senescent cells. Systemic infusion of mesenchymal stem cell-derived apoVs can effectively rescue apoptotic resistance and eliminate senescent cells in mechanical unloading mice.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4000,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373628/pdf/","citationCount":"0","resultStr":"{\"title\":\"Apoptotic vesicle-mediated senolytics requires mechanical loading.\",\"authors\":\"Zhulin Xue, Yexiang Jiang, Bowen Meng, Lu Lu, Meng Hao, Yi Zhang, Songtao Shi, Zili Li, Xueli Mao\",\"doi\":\"10.7150/thno.98763\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Rationale:</b> Mechanical force plays crucial roles in extracellular vesicle biogenesis, release, composition and activity. 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引用次数: 0
摘要
理由机械力在细胞外囊泡的生物生成、释放、组成和活动中发挥着至关重要的作用。然而,机械力是否能调节凋亡小泡(apoptotic vesicle,apoV)的产生尚不清楚。研究方法使用后肢卸载(HU)小鼠模型,通过形态学、大小分布、产量和蛋白质质谱分析,评估了机械卸载对骨髓细胞外囊泡的影响。利用体内 HU 小鼠模型和体外细胞微重力模型评估了抗凋亡和衰老相关表型。通过微计算机断层扫描、组织化学和免疫组织化学以及组织形态学分析,评估了apoVs对HU小鼠模型的治疗效果。使用 SiRNA 和化学药剂进行功能增益和功能缺失检测。结果本研究表明,由于 Piezo1 表达下调和钙离子流入减少,机械力丧失导致细胞凋亡抵抗和衰老相关表型,从而减少了循环中载脂蛋白V的数量。而全身输注apoVs能够挽救Piezo1的表达和钙离子的流入,从而挽救机械卸载诱导的细胞凋亡抵抗和衰老细胞积累。结论:本研究发现了机械力在维持细胞凋亡平衡和消除衰老细胞中的一种未知作用。全身输注间充质干细胞衍生的apoVs可有效挽救机械卸载小鼠的细胞凋亡抵抗并消除衰老细胞。
Rationale: Mechanical force plays crucial roles in extracellular vesicle biogenesis, release, composition and activity. However, it is unknown whether mechanical force regulates apoptotic vesicle (apoV) production. Methods: The effects of mechanical unloading on extracellular vesicles of bone marrow were evaluated through morphology, size distribution, yield, and protein mass spectrometry analysis using hindlimb unloading (HU) mouse model. Apoptosis resistance and aging related phenotype were assessed using HU mouse model in vivo and cell microgravity model in vitro. The therapeutic effects of apoVs on HU mouse model were assessed by using microcomputed tomography, histochemical and immunohistochemical, as well as histomorphometry analyses. SiRNA and chemicals were used for gain and loss-of-function assay. Results: In this study, we show that loss of mechanical force led to cellular apoptotic resistance and aging related phenotype, thus reducing the number of apoVs in the circulation due to down-regulated expression of Piezo1 and reduced calcium influx. And systemic infusion of apoVs was able to rescue Piezo1 expression and calcium influx, thereby, rescuing mechanical unloading-induced cellular apoptotic resistance, senescent cell accumulation. Conclusions: This study identified a previously unknown role of mechanical force in maintaining apoptotic homeostasis and eliminating senescent cells. Systemic infusion of mesenchymal stem cell-derived apoVs can effectively rescue apoptotic resistance and eliminate senescent cells in mechanical unloading mice.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.