乳源外泌体研究进展

doi:10.11843/j.issn.0366-6964.2022.04.003

摘要/Abstract

摘要： 外泌体(exosomes)是一种纳米级别的细胞外囊泡，广泛存在于多种动物的组织和体液中，在各种类型的细胞外囊泡中，外泌体作为一个载体可以携带多种具有生物活性的内含物，而这些内含物的分拣是一个受调控的、非随机的过程。近年来，有研究发现，哺乳动物的乳源外泌体通过消化道被吸收后，可以促进幼畜肠道和免疫系统的发育，同时还参与一些疾病的发生发展过程。本文将对外泌体的产生及功能、乳源外泌体的结构、乳源外泌体的提取鉴定以及乳源外泌体的应用加以综述，为进一步研究乳源外泌体奠定基础。

关键词: 乳源外泌体, 功能特性, 应用

Abstract: Exosomes are nano-level extracellular vesicles, which are widely present in the tissues and body fluids of a variety of animals. In various types of extracellular vesicles, exosomes can carry multiple compounds with biological activity. At the same time, the sorting of compounds in exosomes is a regulated and non-random process. In recent years, studies have shown that milk-derived exosomes can promote development of the intestinal and immune system of young animals after being absorbed in digestive tract, and they are also involved in some disease processes. This article reviews the production and function of exosomes, the extraction and identification of milk-derived exosomes, as well as their application of milk exosomes, in order to provide the theoretical foundation for further research on milk-derived exosomes.

Key words: milk-derived exosomes, functional characteristics, application

中图分类号:

S852.2

丁军, 付子琳, 和俊豪, 段晓微, 马露, 卜登攀. 乳源外泌体研究进展[J]. 畜牧兽医学报, 2022, 53(4): 1019-1029.

DING Jun, FU Zilin, HE Junhao, DUAN Xiaowei, MA Lu, BU Dengpan. Research Progress of Milk-derived Exosomes[J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(4): 1019-1029.

参考文献 110

[1]	CABY M P,LANKAR D,VINCENDEAU-SCHERRER C,et al.Exosomal-like vesicles are present in human blood plasma[J].Int Immunol, 2005,17(7):879-887.
[2]	PISITKUN T,SHEN R F,KNEPPER M A.Identification and proteomic profiling of exosomes in human urine[J].Proc Natl Acad Sci USA, 2004,101(36):13368-13373.
[3]	GATTI J L,MÉTAYER S,BELGHAZI M,et al.Identification,proteomic profiling,and origin of ram epididymal fluid exosome-like vesicles[J].Biol Reprod, 2005,72(6):1452-1465.
[4]	MCKELVEY K J,POWELL K L,ASHTON A W,et al.Exosomes:mechanisms of uptake[J].J Circ Biomark, 2015,4:7.
[5]	CORRADO C,RAIMONDO S,CHIESI A,et al.Exosomes as intercellular signaling organelles involved in health and disease:basic science and clinical applications[J].Int J Mol Sci, 2013,14(3):5338-5366.
[6]	ZEMPLENI J,SUKREET S,ZHOU F,et al.Milk-derived exosomes and metabolic regulation[J].Annu Rev Anim Biosci, 2019,7:245-262.
[7]	LÖTVALL J,HILL A F,HOCHBERG F,et al.Minimal experimental requirements for definition of extracellular vesicles and their functions:a position statement from the international society for extracellular vesicles[J].J Extracell Vesicles, 2014,3(1):26913.
[8]	PAN B T,JOHNSTONE R M.Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro :selective externalization of the receptor[J].Cell, 1983,33(3):967-978.
[9]	HUANG X Y,YUAN T Z,TSCHANNEN M,et al.Characterization of human plasma-derived exosomal RNAs by deep sequencing[J].BMC Genomics, 2013,14:319.
[10]	ISAAC R, REIS F, YING W, et al. Exosomes as mediators of intercellular crosstalk in metabolism[J]. Cell Metab, 2021, 33(9): 1744-1762.
[11]	KALRA H,SIMPSON R J,JI H,et al.Vesiclepedia:a compendium for extracellular vesicles with continuous community annotation[J].PLoS Biol, 2012,10(12):e1001450.
[12]	KALLURI R,LEBLEU V S.Discovery of double-stranded genomic DNA in circulating exosomes[J].Cold Spring Harb Symp Quant Biol, 2016,81:275-280.
[13]	MANCA S,UPADHYAYA B,MUTAI E,et al.Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns[J].Sci Rep, 2018,8(1):11321.
[14]	MUNAGALA R,AQIL F,JEYABALAN J,et al.Bovine milk-derived exosomes for drug delivery[J].Cancer Lett, 2016,371(1):48-61.
[15]	窦庚,刘世宇,金岩.细胞外囊泡在组织工程研究中的新应用[J].口腔生物医学,2020,11(1):1-8.DOU G,LIU S Y,JIN Y.New application of extracellular vesicles in tissue engineering research[J].Oral Biomedicine, 2020,11(1):1-8.(in Chinese)
[16]	BELLINGHAM S A,GUO B B,COLEMAN B M,et al.Exosomes:vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?[J].Front Physiol, 2012,3:124.
[17]	ANDRÁS I E,TOBOREK M.Extracellular vesicles of the blood-brain barrier[J].Tissue Barriers, 2016,4(1):e1131804.
[18]	VELLA L J,HILL A F,CHENG L.Focus on Extracellular Vesicles:exosomes and their role in protein trafficking and biomarker potential in Alzheimer’s and Parkinson’s disease[J].Int J Mol Sci, 2016,17(2):173.
[19]	BADAWY A A,EL-MAGD M A,ALSADRAH S A.Therapeutic effect of camel milk and its exosomes on MCF7 cells in vitro and in vivo [J].Integr Cancer Ther, 2018,17(4):1235-1246.
[20]	DUIJVESZ D,LUIDER T,BANGMA C H,et al.Exosomes as biomarker treasure chests for prostate cancer[J].Eur Urol, 2011,59(5):823-831.
[21]	YÁÑEZ-MÓ M,SILJANDER P R M,ANDREU Z,et al.Biological properties of extracellular vesicles and their physiological functions[J].J Extracell Vesicles, 2015,4(1):27066.
[22]	FUTTER C E, PEARSE A, HEWLETT L J, et al. Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes[J]. J Cell Biol, 1996, 132(6): 1011-1023.
[23]	FUJITA Y,KOSAKA N,ARAYA J,et al.Extracellular vesicles in lung microenvironment and pathogenesis[J].Trends Mol Med, 2015,21(9):533-542.
[24]	TRAJKOVIC K,HSU C,CHIANTIA S,et al.Ceramide triggers budding of exosome vesicles into multivesicular endosomes[J].Science, 2008,319(5867):1244-1247.
[25]	HURLEY J H.ESCRT complexes and the biogenesis of multivesicular bodies[J].Curr Opin Cell Biol, 2008,20(1):4-11.
[26]	BENMOUSSA A,LAUGIER J,BEAUPARLANT C J,et al.Complexity of the microRNA transcriptome of cow milk and milk-derived extracellular vesicles isolated via differential ultracentrifugation[J].J Dairy Sci, 2020,103(1):16-29.
[27]	HATA T,MURAKAMI K,NAKATANI H,et al.Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs[J].Biochem Biophys Res Commun, 2010,396(2):528-533.
[28]	ZHANG M H,MA Z H,LI R,et al.Proteomic analysis reveals proteins and pathways associated with lactation in bovine mammary epithelial cell-derived exosomes[J].J Proteome Res, 2020,19(8):3211-3219.
[29]	HAUG A,HØSTMARK A T,HARSTAD O M.Bovine milk in human nutrition-a review[J].Lipids Health Dis, 2007,6:25.
[30]	MIYAKE H,LEE C,CHUSILP S,et al.Human breast milk exosomes attenuate intestinal damage[J].Pediatr Surg Int, 2020,36(2):155-163.
[31]	CHEN T,XI Q Y,YE R S,et al.Exploration of microRNAs in porcine milk exosomes[J].BMC Genomics, 2014,15:100.
[32]	REINHARDT T A,LIPPOLIS J D,NONNECKE B J,et al.Bovine milk exosome proteome[J].J Proteomics, 2012,75(5):1486-1492.
[33]	TAYLOR D D,GERCEL-TAYLOR C.Exosome platform for diagnosis and monitoring of traumatic brain injury[J].Philos Trans R Soc Lond B Biol Sci, 2014,369(1652):1-10.
[34]	CHAUHAN S,DANIELSON S,CLEMENTS V,et al.Surface glycoproteins of exosomes shed by myeloid-derived suppressor cells contribute to function[J].J Proteome Res, 2017,16(1):238-246.
[35]	MATHIVANAN S,FAHNER C J,REID G E,et al.ExoCarta 2012:database of exosomal proteins,RNA and lipids[J].Nucleic Acids Res, 2012,40(D1):D1241-D1244.
[36]	PATHAN M, FONSEKA P, CHITTI S V, et al. Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles[J]. Nucleic Acids Res, 2019, 47(D1): D516-D519.
[37]	张驰.外泌体在胰腺癌中的研究进展[D].重庆:重庆医科大学,2020.ZHANG C.Advances of exosomes in pancreatic cancer[D].Chongqing:Chongqing Medical University,2020.(in Chinese)
[38]	ZEMPLENI J,AGUILAR-LOZANO A,SADRI M,et al.Biological activities of extracellular vesicles and their cargos from bovine and human milk in humans and implications for infants[J].J Nutr, 2017,147(1):3-10.
[39]	VAN HERWIJNEN M J C,ZONNEVELD M I,GOERDAYAL S,et al.Comprehensive proteomic analysis of human milk-derived extracellular vesicles unveils a novel functional proteome distinct from other milk components[J].Mol Cell Proteomics, 2016,15(11):3412-3423.
[40]	RAPOSO G,STOORVOGEL W.Extracellular vesicles:exosomes,microvesicles,and friends[J].J Cell Biol, 2013,200(4):373-383.
[41]	IZUMI H,TSUDA M,SATO Y,et al.Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages[J].J Dairy Sci, 2015,98(5):2920-2933.
[42]	SUN J J,ASWATH K,SCHROEDER S G,et al.MicroRNA expression profiles of bovine milk exosomes in response to Staphylococcus aureus infection[J].BMC Genomics, 2015,16:806.
[43]	CHEN X,GAO C,LI H J,et al.Identification and characterization of microRNAs in raw milk during different periods of lactation,commercial fluid,and powdered milk products[J].Cell Re s,2010,20(10):1128-1137.
[44]	MUNCH E M,HARRIS R A,MOHAMMAD M,et al.Transcriptome profiling of microRNA by Next-Gen deep sequencing reveals known and novel miRNA species in the lipid fraction of human breast milk[J].PLoS One, 2013,8(2):e50564.
[45]	林德麟,陈婷,黎梦,等.乳中miRNA的研究进展[J].畜牧兽医学报,2016,47(9):1739-1748.LIN D L,CHEN T,LI M,et al.Research progress of miRNA in milk[J].Acta Veterinaria et Zootechnica Sinica, 2016,47(9):1739-1748.(in Chinese)
[46]	GU Y R,LI M Z,WANG T,et al.Lactation-related microRNA expression profiles of porcine breast milk exosomes[J].PLoS One, 2012,7(8):e43691.
[47]	CHEN W J,CHEN X H,QIAN Y,et al.Lipidomic profiling of human milk derived exosomes and their emerging roles in the prevention of necrotizing enterocolitis[J].Mol Nutr Food Res, 2021,65(10):2000845.
[48]	范士杰,马露,卜登攀.差速超速离心法与试剂盒法提取娟姗牛乳源性外泌体的分析比较[J].动物营养学报,2020,32(11):5441-5447.FAN S J,MA L,BU D P.Comparison of jersey milk derived exosomes extracted by differential ultracentrifugation method and kit extraction Method[J].Chinese Journal of Animal Nutrition, 2020,32(11):5441-5447.(in Chinese)
[49]	郝海宁,仝令君,张兰威,等.乳源外泌体的提取及鉴定方法研究进展[J].食品安全质量检测学报,2019,10(14):4582-4588.HAO H N,TONG L J,ZHANG L W,et al.Advances in extraction and identification methods of milk-derived exosomes[J].Journal of Food Safety & Quality, 2019,10(14):4582-4588.(in Chinese)
[50]	ABRAMOWICZ A,WIDLAK P,PIETROWSKA M.Proteomic analysis of exosomal cargo:the challenge of high purity vesicle isolation[J].Mol Biosyst, 2016,12(5):1407-1419.
[51]	WITWER K W,BUZÁS E I,BEMIS L T,et al.Standardization of sample collection,isolation and analysis methods in extracellular vesicle research[J].J Extracell Vesicles, 2013,2(1):20360.
[52]	BUSCHMANN D,KIRCHNER B,HERMANN S,et al.Evaluation of serum extracellular vesicle isolation methods for profiling miRNAs by next-generation sequencing[J].J Extracell Vesicles, 2018,7(1):1481321.
[53]	权素玉,南雪梅,蒋林树,等.动物外泌体的生物学功能研究进展[J].动物营养学报,2018,30(12):4786-4791.QUAN S Y,NAN X M,JIANG L S,et al.Advances in biological functions of animal exosomes[J].Chinese Journal of Animal Nutrition, 2018,30(12):4786-4791.(in Chinese)
[54]	BORIACHEK K,ISLAM M N,MÖLLER A,et al.Biological functions and current advances in isolation and detection strategies for exosome nanovesicles[J].Small, 2018,14(6):1702153.
[55]	SOMIYA M,YOSHIOKA Y,OCHIYA T.Biocompatibility of highly purified bovine milk-derived extracellular vesicles[J].J Extracell Vesicles, 2018,7(1):1440132.
[56]	郝海宁,仝令君,张兰威,等.2种不同牛乳外泌体提取方法的比较研究[J].食品安全质量检测学报,2020,11(8):2569-2574.HAO H N,TONG L J,ZHANG L W,et al.Comparative study of 2 kinds of different extraction methods of bovine milk exosomes[J].Journal of Food Safety and Quality, 2020,11(8):2569-2574.(in Chinese)
[57]	BLANS K,HANSEN M S,SØRENSEN L V,et al.Pellet-free isolation of human and bovine milk extracellular vesicles by size-exclusion chromatography[J].J Extracell Vesicles, 2017,6(1):1294340.
[58]	周志立,黄桂东,钟先锋,等.牛乳来源外泌体的生物学功能研究进展[J].食品工业科技,2021,42(11):372-381.ZHOU Z L,HUANG G D,ZHONG X F,et al.Research progress on biological functions of exosomes derived from bovine milk[J].Science and Technology of Food Industry, 2021,42(11):372-381.(in Chinese)
[59]	SHAO H L,IM H,CASTRO C M,et al.New technologies for analysis of extracellular vesicles[J].Chem Rev, 2018,118(4):1917-1950.
[60]	DRAGOVIC R A,GARDINER C,BROOKS A S,et al.Sizing and phenotyping of cellular vesicles using Nanoparticle Tracking Analysis[J].Nanomedicine, 2011,7(6):780-788.
[61]	DRAGOVIC R A,COLLETT G P,HOLE P,et al.Isolation of syncytiotrophoblast microvesicles and exosomes and their characterisation by multicolour flow cytometry and fluorescence Nanoparticle Tracking Analysis[J].Methods, 2015,87:64-74.
[62]	VAN DER POL E,HOEKSTRA A G,STURK A,et al.Optical and non-optical methods for detection and characterization of microparticles and exosomes[J].J Thromb Haemost, 2010,8(12):2596-2607.
[63]	ARNTZ O J,PIETERS B C H,OLIVEIRA M C,et al.Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models[J].Mol Nutr Food Res, 2015,59(9):1701-1712.
[64]	CAÑÓN-BELTRÁN K,HAMDI M,MAZZARELLA R,et al.Isolation,characterization,and microRNA analysis of extracellular vesicles from bovine oviduct and uterine fluids[J].Methods Mol Biol, 2021,2273:219-238.
[65]	COLITTI M,SGORLON S,STEFANON B.Exosome cargo in milk as a potential marker of cow health[J].J Dairy Res, 2020,87(S1):79-83.
[66]	应易恬,杨璟,严冰璇,等.乳腺炎对牛奶外泌体功能的影响:基于乳腺上皮细胞的观察[J].浙江大学学报:农业与生命科学版,2020,46(3):383-390.YING Y T,YANG J,YAN B X,et al.Effect of mastitis on the function of milk-derived exosomes:observations from mammary epithelial cells[J].Journal of Zhejiang University:Agriculture & Life Sciences, 2020,46(3):383-390.(in Chinese)
[67]	CAI M C,HE H B,JIA X B,et al.Genome-wide microRNA profiling of bovine milk-derived exosomes infected with Staphylococcus aureus[J].Cell Stress Chaperones, 2018,23(4):663-672.
[68]	童超.外泌体miRNA和lncRNA作为奶牛乳腺炎分子标记的筛选和功能鉴定[D].杨凌:西北农林科技大学,2017.TONG C.Screening and characterization of exosomal miRNA and lncRNAs as biomarkers in bovine mastitis[D].Yangling:Northwest A＆F University,2017.(in Chinese)
[69]	张修奇.奶牛乳源外泌体分离及乳房炎相关miRNAs的鉴定[D].长春:吉林大学,2020.ZHANG X Q.Isolation of milk-derived exosomes and identification of miRNAs associated with mastitis[D].Changchun:Jilin University,2020.(in Chinese)
[70]	吴金恩,丁军涛.外泌体生物学功能及应用研究进展[J].动物医学进展,2016,37(12):90-94.WU J E,DING J T.Progress on biological function and application of exosomes[J].Progress in Veterinary Medicine, 2016,37(12):90-94.(in Chinese)
[71]	RAPOSO G,NIJMAN H W,STOORVOGEL W,et al.B lymphocytes secrete antigen-presenting vesicles[J].J Exp Med, 1996,183(3):1161-1172.
[72]	姜承耀,陈文娟,陈小慧,等.母乳外泌体载药用于新生儿相关疾病治疗的研究进展[J].医学综述,2020,26(19):3769-3773,3779.JIANG C Y,CHEN W J,CHEN X H,et al.Research progress of breast milk exosome-loaded drugs for treatment of neonatal related diseases[J].Medical Recapitulate, 2020,26(19):3769-3773,3779.(in Chinese)
[73]	MENG W R,HE C S,HAO Y Y,et al.Prospects and challenges of extracellular vesicle-based drug delivery system:considering cell source[J].Drug Deliv, 2020,27(1):585-598.
[74]	AGRAWAL A K,AQIL F,JEYABALAN J,et al.Milk-derived exosomes for oral delivery of paclitaxel[J].Nanomedicine, 2017,13(5):1627-1636.
[75]	KAMERKAR S,LEBLEU V S,SUGIMOTO H,et al.Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer[J].Nature, 2017,546(7659):498-503.
[76]	KIM G,LEE Y,HA J,et al.Engineering exosomes for pulmonary delivery of peptides and drugs to inflammatory lung cells by inhalation[J].J Controlled Release, 2021,330:684-695.
[77]	VINAIPHAT A,SZE S K.Advances in extracellular vesicles analysis[J].Adv Clin Chem, 2020,97:73-116.
[78]	周昌娈,谭磊,丁铲.RNA病毒利用外泌体促进病毒感染的研究进展[J].微生物学通报,2017,44(12):2988-2996.ZHOU C L,TAN L,DING C.Advances of RNA virus increasing viral infection through the exosomes[J].Microbiology China, 2017,44(12):2988-2996.(in Chinese)
[79]	NÄSLUND T I,PAQUIN-PROULX D,PAREDES P T,et al.Exosomes from breast milk inhibit HIV-1 infection of dendritic cells and subsequent viral transfer to CD4+ T cells[J].AIDS, 2014,28(2):171-180.
[80]	YUN B,MABURUTSE B E,KANG M,et al.Short communication :dietary bovine milk-derived exosomes improve bone health in an osteoporosis-induced mouse model[J].J Dairy Sci, 2020,103(9):7752-7760.
[81]	CHENG P,CHEN C,HE H B,et al.miR-148a regulates osteoclastogenesis by targeting V-maf musculoaponeurotic fibrosarcoma oncogene homolog B[J].J Bone Miner Res, 2013,28(5):1180-1190.
[82]	LIAO J,LIU R,SHI Y J,et al.Exosome-shuttling microRNA-21 promotes cell migration and invasion-targeting PDCD4 in esophageal cancer[J].Int J Oncol, 2016,48(6):2567-2579.
[83]	QUINN J M W,ITOH K,UDAGAWA N,et al.Transforming growth factor β affects osteoclast differentiation via direct and indirect actions[J].J Bone Miner Res, 2001,16(10):1787-1794.
[84]	GAO H N,HU H,WEN P C,et al.Yak milk-derived exosome alleviates lipopolysaccharide-induced intestinal inflammation by inhibiting PI3K/AKT/C3 pathway activation[J].J Dairy Sci, 2021,104(8):8411-8424.
[85]	QIN W Y,TSUKASAKI Y,DASGUPTA S,et al.Exosomes in human breast milk promote EMT[J].Clin Cancer Res, 2016,22(17):4517-4524.
[86]	MELNIK B C.Dairy consumption and hepatocellular carcinoma risk[J].Ann Transl Med, 2021,9(8):736.
[87]	BODO C M,GERD S.Exosomes of pasteurized milk:potential pathogens of Western diseases[J].J Transl Med, 2019,17(1):3.
[88]	YU B Q,LV X,SU L P,et al.MiR-148a Functions as a tumor suppressor by targeting CCK-BR via inactivating STAT3 and Akt in human gastric cancer[J].PLoS One, 2016,11(8):e0158961.
[89]	SHI C M,ZHANG M,TONG M L,et al.miR-148a is associated with obesity and modulates adipocyte differentiation of mesenchymal stem cells through Wnt signaling[J].Sci Rep, 2015,5:9930.
[90]	KANG M,YAN L M,ZHANG W Y,et al.Role of microRNA-21 in regulating 3T3-L1 adipocyte differentiation and adiponectin expression[J].Mol Biol Rep, 2013,40(8):5027-5034.
[91]	JIANG H,WU W,ZHANG M,et al.Aberrant upregulation of miR-21 in placental tissues of macrosomia[J].J Perinatol, 2014,34(9):658-663.
[92]	JI R R,CHENG Y H,YUE J M,et al.MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation[J].Circ Res, 2007,100(11):1579-1588.
[93]	AHMADVAND M,ESKANDARI M,PASHAIEFAR H,et al.Over expression of circulating miR-155 predicts prognosis in diffuse large B-cell lymphoma[J].Leuk Res, 2018,70:45-48.
[94]	WANG X S,PENG L,GONG X J,et al.miR-423-5p inhibits osteosarcoma proliferation and invasion through directly targeting STMN1[J].Cell Physiol Biochem, 2018,50(6):2249-2259.
[95]	KIM H K,PARK J D,CHOI S H,et al.Functional link between miR-200a and ELK3 regulates the metastatic nature of breast cancer[J].Cancers (Basel), 2020,12(5):1225.
[96]	LIU H B,CHENG Y,XU Y P,et al.The inhibition of tumor protein p53 by microRNA-151a-3p induced cell proliferation,migration and invasion in nasopharyngeal carcinoma[J].Biosci Rep, 2019,39(10):BSR20191357.
[97]	ZHANG J W,WANG X,LI G C,et al.MiR-30a-5p promotes cholangiocarcinoma cell proliferation through targeting SOCS3[J].J Cancer, 2020,11(12):3604-3614.
[98]	ADMYRE C,JOHANSSON S M,QAZI K R,et al.Exosomes with immune modulatory features are present in human breast milk[J].J Immunol, 2007,179(3):1969-1978.
[99]	MUNBLIT D,PERONI D G,BOIX-AMORÓS A,et al.Human milk and allergic diseases:an unsolved puzzle[J].Nutrients, 2017,9(8):894.
[100]	BAIER S R,NGUYEN C,XIE F,et al.MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells,HEK-293 kidney cell cultures,and mouse livers[J].J Nutr, 2014,144(10):1495-1500.
[101]	ZHONG J, XIA B, SHAN S, et al. High-quality milk exosomes as oral drug delivery system[J]. Biomaterials ， 2021, 277: 121126.
[102]	GARCIA C,DUAN R D,BRÉVAUT-MALATY V,et al.Bioactive compounds in human milk and intestinal health and maturity in preterm newborn:an overview[J].Cell Mol Biol (Noisy-le-grand), 2013,59(1):108-131.
[103]	RANI P,VASHISHT M,GOLLA N,et al.Milk miRNAs encapsulated in exosomes are stable to human digestion and permeable to intestinal barrier in vitro [J].J Funct Foods, 2017,34:431-439.
[104]	CHEN T,XIE M Y,SUN J J,et al.Porcine milk-derived exosomes promote proliferation of intestinal epithelial cells[J].Sci Rep, 2016,6:33862.
[105]	MAGHRABY M K,LI B,CHI L J,et al.Extracellular vesicles isolated from milk can improve gut barrier dysfunction induced by malnutrition[J].Sci Rep, 2021,11(1):7635.
[106]	高海娜.牦牛乳外泌体miRNA缓解小肠上皮细胞缺氧损伤的作用机制[D].兰州:甘肃农业大学,2019.GAO H N.Study of the mechanism for yak milk exosomal miRNAs in alleviating hypoxia injury of intestinal epithelial cells[D].Lanzhou:Gansu Agricultural University,2019.(in Chinese)
[107]	GAO H N,GUO H Y,ZHANG H,et al.Yak-milk-derived exosomes promote proliferation of intestinal epithelial cells in an hypoxic environment[J].J Dairy Sci, 2019,102(2):985-996.
[108]	ZHOU Y H,YU Z B,WANG X Y,et al.Exosomal circRNAs contribute to intestinal development via the VEGF signalling pathway in human term and preterm colostrum[J].Aging (Albany NY), 2021,13(8):11218-11233.
[109]	ZENG B,WANG H L,LUO J Y,et al.Porcine milk-derived small extracellular vesicles promote intestinal immunoglobulin production through pIgR[J].Animals (Basel ),2021,11(6):1522.
[110]	ZHOU F,PAZ H A,SADRI M,et al.Dietary bovine milk exosomes elicit changes in bacterial communities in C57BL/6 mice[J].Am J Physiol Gastrointest Liver Physiol, 2019,317(5):G618-G624.