胞外囊泡在恶性肿瘤发生发展中的作用

通过胞外囊泡(extracellular vesicles,Evs)进行的细胞内信号转导是一种被低估的细胞间的沟通方式.EVs携带很多生物活性分子、表面受体以及基因信息,例如蛋白编码基因和miRNAs,lncRNAs以及mRNAs都可通过EVs在细胞间传递并且影响受体细胞的功能.本篇文章阐述了EVs,尤其是EVs相关的miRNAs如何影响恶性肿瘤的发生、侵袭、转移和复发.     

Role of extracellular vesicles in osteosarcoma

Osteosarcoma is a malignant bone tumor characterized by the direct production of osteoid tissue from tumor cells. Extracellular vesicles are membranous vesicles released by cells into the extracellular matrix, which exist widely in various body fluids and cell supernatants, and stably carry some important signaling molecules. They are involved in cell communication, cell migration, angiogenesis and tumor cell growth. Increasing evidence has shown that extracellular vesicles play a significant role in osteosarcoma development, progression, and metastatic process, indicating that extracellular vesicles can be use as biomarker vehicles in the diagnosis and prognosis of osteosarcoma. This review discusses the basic biological characteristics of extracellular vesicles and focuses on their application in osteosarcoma.     

Diet,commensal microbiota-derived extracellular vesicles,and host immunity

The gut microbiota has co-evolved with its host, and commensal bacteria can influence both the host's immune development and function. Recently, a role has emerged for bacterial extracellular vesicles (BEVs) as potent immune modulators. BEVs are nanosized membrane vesicles produced by all bacteria, possessing the membrane characteristics of the originating bacterium and carrying an internal cargo that may include nucleic acid, proteins, lipids, and metabolites. Thus, BEVs possess multiple avenues for regulating immune processes, and have been implicated in allergic, autoimmune, and metabolic diseases. BEVs are biodistributed locally in the gut, and also systemically, and thus have the potential to affect both the local and systemic immune responses. The production of gut microbiota-derived BEVs is regulated by host factors such as diet and antibiotic usage. Specifically, all aspects of nutrition, including macronutrients (protein, carbohydrates, and fat), micronutrients (vitamins and minerals), and food additives (the antimicrobial sodium benzoate), can regulate BEV production. This review summarizes current knowledge of the powerful links between nutrition, antibiotics, gut microbiota-derived BEV, and their effects on immunity and disease development. It highlights the potential of targeting or utilizing gut microbiota-derived BEV as a therapeutic intervention.     

Transfer of extracellular vesicles during immune cell-cell interactions

The transfer of molecules between cells during cognate immune cell interactions has been reported, and recently a novel mechanism of transfer of proteins and genetic material such as small RNA between T cells and antigen-presenting cells (APCs) has been described, involving exchange of extracellular vesicles (EVs) during the formation of the immunological synapse (IS). EVs, a term that encompasses exosomes and microvesicles, has been implicated in cell-cell communication during immune responses associated with tumors, pathogens, allergies, and autoimmune diseases. This review focuses on EV transfer as a mechanism for the exchange of molecules during immune cell-cell interactions.     

Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: From immunomodulation to therapy

Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC-sEV is an obstacle for clinical applications. The potential application of MSC-sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC-sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC-sEV, and the methods for obtaining high-quality human MSC-sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC-sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation.     

Endothelial extracellular vesicles modulate the macrophage phenotype: Potential implications in atherosclerosis

Endothelial cells (EC s) and macrophages engage in tight and specific interactions that play critical roles in cardiovascular homeostasis and the pathogenesis of atherosclerosis. Extracellular vesicles (EV s) are circular membrane fragments released from the endosomal compartment as exosomes or shed from the surfaces of the membranes of most cell types. Increasing evidence indicates that EV s play a pivotal role in cell‐to‐cell communication. However, the contribution of EV s, as determine by oxidized low‐density lipoprotein (ox‐LDL )‐exposed and/or Kruppel‐like factor 2 (KLF 2)‐transduced EC s in the interaction between vascular EC s and monocytes/macrophages, which is a key event in atherosclerotic plaque development, has remained elusive. This study demonstrates the characteristic impact of EV s from ox‐LDL ‐treated and/or KLF 2‐transduced EC s on the monocyte/macrophage phenotype in vitro and in vivo.Q‐PCR showed that both the atherosclerosis inducer ox‐LDL and atheroprotective factor KLF 2 regulated inflammation‐associated microRNA ‐155 (miR‐155) expression in human umbilical vein endothelial cells (HUVEC s). Moreover, coculture, immunofluorescence and flow cytometry revealed that miR‐155 was enriched in ox‐LDL ‐induced EC s‐EV s and subsequently transferred to human monocytic THP 1 cells, in which these vesicles enhance monocyte activation by shifting the monocytes/macrophages balance from anti‐inflammatory M2 macrophages towards proinflammatory M1 macrophages; EV s from KLF 2‐expressing EC s suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses, which indicate the potent anti‐inflammatory activities of these cells. Furthermore, oil red staining showed that atherosclerotic lesions were reduced in mice that received EV s from KLF 2‐transduced EC s with decreased proinflammatory M1 macrophages and increased anti‐inflammatory M2 macrophages, and this effect is at least partly due to the decreased expression of inflammation‐associated miR‐155, confirming our in vitro findings. In summary, this study provides novel insights into the pathophysiological effects of altered EV secretion and/or microRNA content and their influence on modulating monocyte activation depending on the environment surrounding EV s‐releasing EC s.

     

细胞外囊泡与放射性组织损伤的关系

背景:放射性组织损伤是癌症患者放疗后出现较为严重的不良反应之一.最近研究表明,在放射性组织损伤模型中,作为细胞间信息载体的细胞外囊泡有其两面性,一方面通过参与放射性组织损伤过程来介导组织损伤,另一方面还通过转移生物活性物质参与放射性组织损伤修复.目的:文章综述不同来源细胞外囊泡对放射性组织损伤的危害和修复作用,阐明细胞...     

Proteomic profiling of extracellular vesicles released from vascular smooth muscle cells during initiation of phosphate-induced mineralization

ABSTRACT

Purpose/Aim: Elevated serum phosphate is one of the major factors contributing to vascular calcification. Studies suggested that extracellular vesicles released from vascular smooth muscle cells significantly contribute to the initiation and progression of this pathology. Recently, we have demonstrated that elevated phosphate stimulates release of extracellular vesicles from osteogenic cells at the initiation of the mineralization process. Here, we used MOVAS cell line as an in vitro model of vascular calcification to examine whether vascular smooth muscle cells respond to high phosphate levels in a similar way and increase formation of extracellular vesicles. Materials and Methods: Vesicles residing in extracellular matrix as well as vesicles released to culture medium were evaluated by nanoparticle tracking analyses. In addition, using mass spectrometry and protein profiling, protein composition of extracellular vesicles released by MOVAS cells under standard growth conditions and upon exposure to high phosphate was compared. Results: Significant increase of the number of extracellular vesicles was detected after 72 h of exposure of cells to high phosphate. Elevated phosphate levels also affected protein composition of extracellular vesicles released from MOVAS cells. Finally, the comparative analyses of proteins in extracellular vesicles isolated from extracellular matrix and from conditioned medium identified significant differences in protein composition in these two groups of extracellular vesicles. Conclusions: Results of this study demonstrate that exposure of MOVAS cells to high phosphate levels stimulates the release of extracellular vesicles and changes their protein composition.     

Tamoxifen modulates cell migration and expression of angiogenesis-related genes in human endometrial endothelial cells

The selective estrogen receptor modulator tamoxifen is used for the prevention and treatment of breast cancer. The adverse effects of tamoxifen include vaginal endometrial bleeding, endometrial hyperplasia, and cancer, conditions associated with angiogenesis. The aim of this study was to examine the effects of tamoxifen on cell migration and angiogenesis-related gene expression in human endometrial endothelial cells (HEECs). The regulatory effects of tamoxifen on endometrial stromal cells and HEECs were also examined. HEECs and stromal cells were isolated and grown in monocultures or co-cultures, and incubated with 0.1 to 100 μmol/L tamoxifen for 48 hours. Quantitative PCR demonstrated that tamoxifen decreased the mRNA expression of vascular endothelial growth factor-A (VEGF-A) and increased the mRNA expression of VEGF receptor-1 and placental growth factor (PLGF) in HEECs. Tamoxifen's effects on VEGF-A were inhibited when HEECs were co-cultured with stromal cells. In addition, tamoxifen reduced VEGF-induced HEEC migration. The tamoxifen-metabolizing enzymes CYP1A1 and CYP1B1 were detected by immunohistochemistry in and around endometrial blood vessels and by quantitative PCR in HEECs. Our data suggest that tamoxifen changes the regulation of angiogenesis in the endometrium, likely by reducing angiogenic activity. The results also indicate that endometrial stromal cells regulate some of tamoxifen's effects in HEECs, and the presence of tamoxifen-metabolizing enzymes suggests tamoxifen bioactivation in the endometrial vasculature in vivo. These findings may help to elucidate the mechanism of the bleeding disturbances associated with tamoxifen treatment.     

热休克内皮细胞诱导骨髓间充质干细胞向血管内皮细胞分化

文题释义：血管内皮细胞：研究中一般称内皮细胞,通常指衬于心、血管和淋巴管内表面的单层扁平上皮,它形成血管的内壁。它们具有吞噬异物、细菌、坏死和衰老组织的功能,还参与机体免疫活动功能。 热休克：组织工程中一种细胞处理方法,将细胞置于42 ℃(也有文献报道为47 ℃)中1 h,造成热休克状态。 背景：目前关于间充质干细胞向内皮细胞分化的研究,多采用细胞因子或2种细胞共培养的方法进行诱导,热休克处理的内皮细胞诱导间充质干细胞向内皮细胞分化尚未见报道。 目的：观察热休克处理的人脐静脉内皮细胞诱导骨髓间充质干细胞向血管内皮细胞分化的能力,并探究诱导骨髓间充质干细胞形成血管的能力。 方法：将热休克处理后的人脐静脉内皮细胞与人骨髓间充质干细胞体外非接触共培养,诱导14 d后采用流式细胞仪和免疫荧光检测骨髓间充质干细胞中CD144、CD31、VEGFR2、vWF表型的表达;将诱导14 d后的骨髓间充质干细胞、未诱导的骨髓间充质干细胞移植到裸鼠皮下,14 d后取移植物做苏木精-伊红染色,观察体内血管形成能力;Matrigel成血管实验观察诱导14 d后的骨髓间充质干细胞和未诱导的骨髓间充质干细胞的体外血管生成能力。 结果与结论：①共培养后骨髓间充质干细胞形态改变,呈类似铺路石状排列,流式细胞仪及细胞免疫荧光结果显示共培养后骨髓间充质干细胞VEGFR2、CD31、CD144、vWF表达增加;②体内移植物苏木精-伊红染色显示诱导后的骨髓间充质干细胞排列较对照组规律,有成血管倾向;③体外Matrigel成血管实验显示诱导后骨髓间充质干细胞成血管能力较对照组有所增加;④结果表明,与热休克处理的人脐静脉内皮细胞共培养能促进人骨髓间充质干细胞向内皮细胞分化,内皮细胞特异性表型转化较明显,具有一定血管形成倾向。 ORCID: 0000-0003-4089-8882(曹百川) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

The occurrence of extracellular matrix vesicles in pulmonary alveolar microlithiasis

Summary Mineralization in pulmonary alveolar microlithiasis was studied by transmission electron microscopy. The disease is characterized by psammoma like calcifications composed of hydroxyapatite crystals. The calcifications were surrounded by typical forming cells and matrix composed of collagen fibers arranged in a longitudinal pattern. Abundant calcifying extracellular matrix vesicles were found between the cells and the calcified fronts. The type of calcification found in the present lesion is similar to ectopic primary mineralization in other diseases, embryonal ossification and bone wound healing.This study was supported by a grant from the Government of Israel, The Ministry of Health