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循环中的细胞外囊泡在人类疾病中的作用
Circulating Extracellular Vesicles in Human Disease


Ravi Shah ... 心脑血管疾病 肿瘤 • 2018.09.06

众所周知,细胞在细胞死亡或凋亡期间,会向细胞外环境释放出充满液体的囊(囊泡),但人们越来越多地认识到健康细胞在发挥正常功能的过程中也可能释放出囊泡。由健康细胞释放的囊泡具有多种名称(例如核外粒体[ectosome]、微粒[microparticle]、微泡[microvesicle]、外排体[exosome]和癌小体[oncosome]),术语“细胞外囊泡”通常被用作分泌囊泡的总称1。细胞外囊泡见于循环系统中,含有细胞来源的生命分子(例如RNA、蛋白质和代谢物)。细胞外囊泡参与细胞间的分子运输,因此对生理功能有影响,可作为疾病的生物标志物(见视频)。然而,重要的局限性(包括实践中难以测定循环中低浓度的细胞外囊泡,难以鉴定细胞外囊泡的组织来源,难以确定哪种分子货物[molecular cargo]最相关)限制了对细胞外囊泡在体内作用的研究热情。本文的目的包括提供对细胞外囊泡的简要介绍(特别关注转化和临床研究),以突显一些提示细胞外囊泡在人类疾病中有潜在作用的新证据。考虑到这一领域工作的爆发式发展,很难涵盖细胞外囊泡在功能上可能相关的所有疾病。因此,读者可以参考该领域中不断扩展的文献以获得更多详细信息2,3

 

什么是细胞外囊泡


细胞外囊泡是从组织中排出,由膜包绕的细胞器,其内含有不同类型的分子货物(例如RNA、蛋白质和代谢物)。细胞外囊泡的经典二分法依据的是囊泡大小和生物发生。例如,外排体定义为直径<150 nm,而核外粒体或微粒(微泡)定义为直径≤1,000 nm。关于细胞外囊泡的形成,外排体被描述为由多泡体和多种细胞产生。虽然现有文献依据的定义是基于大小,但最近的专家共识已经认识到,对于不同大小的细胞外囊泡,了解其生物发生和分子内容物差异可能很有意义4。目前,细胞外囊泡生物发生的机制和迫使它们被释放的细胞内信号传导途径是正在研究的领域,超出了本综述的范围。我们注意到许多研究专注于外排体;在本综述中,我们提到的“细胞外囊泡”指所有循环细胞外囊泡,并提醒需要进一步研究它们的物理和生化特性。





作者信息

Ravi Shah, M.D., Tushar Patel, M.B., Ch.B., and Jane E. Freedman, M.D.
From the Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (R.S.), and the University of Massachusetts Medical School, Worcester (J.E.F.) — both in Massachusetts; and the Department of Transplantation, Mayo Clinic, Jacksonville, FL (T.P.). Address reprint requests to Dr. Freedman at the University of Massachusetts Medical Center, AS7-1051, 368 Plantation St., Worcester, MA 01605, or at jane.freedman@umassmed.edu.

 

参考文献

1. van der Pol E, Böing AN, Gool EL, Nieuwland R. Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles. J Thromb Haemost 2016;14:48-56.

2. Lener T, Gimona M, Aigner L, et al. Applying extracellular vesicles based therapeutics in clinical trials — an ISEV position paper. J Extracell Vesicles 2015;4:30087-30087.

3. El Andaloussi S, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013;12:347-357.

4. Mateescu B, Kowal EJ, van Balkom BW, et al. Obstacles and opportunities in the functional analysis of extracellular vesicle RNA — an ISEV position paper. J Extracell Vesicles 2017;6:1286095-1286095.

5. Raposo G, Nijman HW, Stoorvogel W, et al. B lymphocytes secrete antigen-presenting vesicles. J Exp Med 1996;183:1161-1172.

6. Robbins PD, Dorronsoro A, Booker CN. Regulation of chronic inflammatory and immune processes by extracellular vesicles. J Clin Invest 2016;126:1173-1180.

7. Shedden K, Xie XT, Chandaroy P, Chang YT, Rosania GR. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profiles. Cancer Res 2003;63:4331-4337.

8. Muralidharan-Chari V, Kohan HG, Asimakopoulos AG, et al. Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells. Oncotarget 2016;7:50365-50379.

9. Ciravolo V, Huber V, Ghedini GC, et al. Potential role of HER2-overexpressing exosomes in countering trastuzumab-based therapy. J Cell Physiol 2012;227:658-667.

10. Au Yeung CL, Co NN, Tsuruga T, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun 2016;7:11150-11150.

11. Jeppesen DK, Nawrocki A, Jensen SG, et al. Quantitative proteomics of fractionated membrane and lumen exosome proteins from isogenic metastatic and nonmetastatic bladder cancer cells reveal differential expression of EMT factors. Proteomics 2014;14:699-712.

12. Costa-Silva B, Aiello NM, Ocean AJ, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 2015;17:816-826.

13. Melo SA, Sugimoto H, O’Connell JT, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 2014;26:707-721.

14. Hong CS, Muller L, Boyiadzis M, Whiteside TL. Isolation and characterization of CD34+ blast-derived exosomes in acute myeloid leukemia. PLoS One 2014;9(8):e103310-e103310.

15. Taylor DD, Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 2008;110:13-21.

16. Ye SB, Li ZL, Luo DH, et al. Tumor-derived exosomes promote tumor progression and T-cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma. Oncotarget 2014;5:5439-5452.

17. Silva J, Garcia V, Rodriguez M, et al. Analysis of exosome release and its prognostic value in human colorectal cancer. Genes Chromosomes Cancer 2012;51:409-418.

18. Sandfeld-Paulsen B, Jakobsen KR, Baek R, et al. Exosomal proteins as diagnostic biomarkers in lung cancer. J Thorac Oncol 2016;11:1701-1710.

19. He M, Zeng Y. Microfluidic exosome analysis toward liquid biopsy for cancer. J Lab Autom 2016;21:599-608.

20. Baran J, Baj-Krzyworzeka M, Weglarczyk K, et al. Circulating tumour-derived microvesicles in plasma of gastric cancer patients. Cancer Immunol Immunother 2010;59:841-850.

21. Arbelaiz A, Azkargorta M, Krawczyk M, et al. Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2017;66:1125-1143.

22. Khan S, Bennit HF, Turay D, et al. Early diagnostic value of survivin and its alternative splice variants in breast cancer. BMC Cancer 2014;14:176-176.

23. Logozzi M, De Milito A, Lugini L, et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS One 2009;4(4):e5219-e5219.

24. Logozzi M, Angelini DF, Iessi E, et al. Increased PSA expression on prostate cancer exosomes in in vitro condition and in cancer patients. Cancer Lett 2017;403:318-329.

25. Nuzhat Z, Kinhal V, Sharma S, Rice GE, Joshi V, Salomon C. Tumour-derived exosomes as a signature of pancreatic cancer — liquid biopsies as indicators of tumour progression. Oncotarget 2017;8:17279-17291.

26. Qu Z, Wu J, Wu J, et al. Exosomal miR-665 as a novel minimally invasive biomarker for hepatocellular carcinoma diagnosis and prognosis. Oncotarget 2017;8:80666-80678.

27. Shiromizu T, Kume H, Ishida M, et al. Quantitation of putative colorectal cancer biomarker candidates in serum extracellular vesicles by targeted proteomics. Sci Rep 2017;7:12782-12782.

28. Rodríguez M, Bajo-Santos C, Hessvik NP, et al. Identification of non-invasive miRNAs biomarkers for prostate cancer by deep sequencing analysis of urinary exosomes. Mol Cancer 2017;16:156-156.

29. Smalley DM, Sheman NE, Nelson K, Theodorescu D. Isolation and identification of potential urinary microparticle biomarkers of bladder cancer. J Proteome Res 2008;7:2088-2096.

30. Akers JC, Hua W, Li H, et al. A cerebrospinal fluid microRNA signature as biomarker for glioblastoma. Oncotarget 2017;8:68769-68779.

31. Tanaka Y, Kamohara H, Kinoshita K, et al. Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer 2013;119:1159-1167.

32. Gilligan KE, Dwyer RM. Engineering exosomes for cancer therapy. Int J Mol Sci 2017;18:18-18.

33. Tang XJ, Sun XY, Huang KM, et al. Therapeutic potential of CAR-T cell-derived exosomes: a cell-free modality for targeted cancer therapy. Oncotarget 2015;6:44179-44190.

34. Kim MS, Haney MJ, Zhao Y, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine 2016;12:655-664.

35. Lyu L, Wang H, Li B, et al. A critical role of cardiac fibroblast-derived exosomes in activating renin angiotensin system in cardiomyocytes. J Mol Cell Cardiol 2015;89:Pt B:268-279.

36. Wang C, Zhang C, Liu L, et al. Macrophage-derived mir-155-containing exosomes suppress fibroblast proliferation and promote fibroblast inflammation during cardiac injury. Mol Ther 2017;25:192-204.

37. Jiang X, Sucharov J, Stauffer BL, Miyamoto SD, Sucharov CC. Exosomes from pediatric dilated cardiomyopathy patients modulate a pathological response in cardiomyocytes. Am J Physiol Heart Circ Physiol 2017;312:H818-H826.

38. Ye W, Tang X, Yang Z, et al. Plasma-derived exosomes contribute to inflammation via the TLR9-NF-κB pathway in chronic heart failure patients. Mol Immunol 2017;87:114-121.

39. Emanueli C, Shearn AI, Laftah A, et al. Coronary artery-bypass-graft surgery increases the plasma concentration of exosomes carrying a cargo of cardiac microRNAs: an example of exosome trafficking out of the human heart with potential for cardiac biomarker discovery. PLoS One 2016;11(4):e0154274-e0154274.

40. Amabile N, Cheng S, Renard JM, et al. Association of circulating endothelial microparticles with cardiometabolic risk factors in the Framingham Heart Study. Eur Heart J 2014;35:2972-2979.

41. Nozaki T, Sugiyama S, Koga H, et al. Significance of a multiple biomarkers strategy including endothelial dysfunction to improve risk stratification for cardiovascular events in patients at high risk for coronary heart disease. J Am Coll Cardiol 2009;54:601-608.

42. Kennel PJ, Saha A, Maldonado DA, et al. Serum exosomal protein profiling for the non-invasive detection of cardiac allograft rejection. J Heart Lung Transplant 2018;37:409-417.

43. Matsumoto S, Sakata Y, Suna S, et al. Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. Circ Res 2013;113:322-326.

44. de Hoog VC, Timmers L, Schoneveld AH, et al. Serum extracellular vesicle protein levels are associated with acute coronary syndrome. Eur Heart J Acute Cardiovasc Care 2013;2:53-60.

45. Kervadec A, Bellamy V, El Harane N, et al. Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure. J Heart Lung Transplant 2016;35:795-807.

46. Khan M, Nickoloff E, Abramova T, et al. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res 2015;117:52-64.

47. Stepanian A, Bourguignat L, Hennou S, et al. Microparticle increase in severe obesity: not related to metabolic syndrome and unchanged after massive weight loss. Obesity (Silver Spring) 2013;21:2236-2243.

48. Thomou T, Mori MA, Dreyfuss JM, et al. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 2017;542:450-455.

49. Jansen F, Wang H, Przybilla D, et al. Vascular endothelial microparticles-incorporated microRNAs are altered in patients with diabetes mellitus. Cardiovasc Diabetol 2016;15:49-49.

50. Hubal MJ, Nadler EP, Ferrante SC, et al. Circulating adipocyte-derived exosomal microRNAs associated with decreased insulin resistance after gastric bypass. Obesity (Silver Spring) 2017;25:102-110.

51. Huang S, Ge X, Yu J, et al. Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. FASEB J 2018;32:512-528.

52. Xin H, Li Y, Buller B, et al. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 2012;30:1556-1564.

53. Ngolab J, Trinh I, Rockenstein E, et al. Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology. Acta Neuropathol Commun 2017;5:46-46.

54. Saman S, Kim W, Raya M, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 2012;287:3842-3849.

55. Asai H, Ikezu S, Tsunoda S, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 2015;18:1584-1593.

56. Goetzl EJ, Abner EL, Jicha GA, Kapogiannis D, Schwartz JB. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer’s disease. FASEB J 2018;32:888-893.

57. Fiandaca MS, Kapogiannis D, Mapstone M, et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement 2015;11(6):600-607.e1.

58. Cheng L, Doecke JD, Sharples RA, et al. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry 2015;20:1188-1196.

59. Gui Y, Liu H, Zhang L, Lv W, Hu X. Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 2015;6:37043-37053.

60. Stern RA, Tripodis Y, Baugh CM, et al. Preliminary study of plasma exosomal tau as a potential biomarker for chronic traumatic encephalopathy. J Alzheimers Dis 2016;51:1099-1109.

61. Ko J, Hemphill MA, Gabrieli D, et al. Smartphone-enabled optofluidic exosome diagnostic for concussion recovery. Sci Rep 2016;6:31215-31215.

62. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011;29:341-345.

63. Raab-Traub N, Dittmer DP. Viral effects on the content and function of extracellular vesicles. Nat Rev Microbiol 2017;15:559-572.

64. Ramakrishnaiah V, Thumann C, Fofana I, et al. Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells. Proc Natl Acad Sci U S A 2013;110:13109-13113.

65. Hubert A, Subra C, Jenabian MA, et al. Elevated abundance, size, and microRNA content of plasma extracellular vesicles in viremic HIV-1+ patients: correlations with known markers of disease progression. J Acquir Immune Defic Syndr 2015;70:219-227.

66. Properzi F, Logozzi M, Abdel-Haq H, et al. Detection of exosomal prions in blood by immunochemistry techniques. J Gen Virol 2015;96:1969-1974.

67. Fevrier B, Vilette D, Archer F, et al. Cells release prions in association with exosomes. Proc Natl Acad Sci U S A 2004;101:9683-9688.

68. Witwer KW, Buzás EI, Bemis LT, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2013;2:2-2.

69. Gardiner C, Di Vizio D, Sahoo S, et al. Techniques used for the isolation and characterization of extracellular vesicles: results of a worldwide survey. J Extracell Vesicles 2016;5:32945-32945.

70. Lobb RJ, Becker M, Wen SW, et al. Optimized exosome isolation protocol for cell culture supernatant and human plasma. J Extracell Vesicles 2015;4:27031-27031.

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