Journal of Prevention and Treatment for Stomatological Diseases ›› 2020, Vol. 28 ›› Issue (1): 1-10.doi: 10.12016/j.issn.2096-1456.2020.01.001

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Research and application of stem cell-derived exosomes in regenerative medicine

YE Qingsong1,2,3(),HU Fengting2,LUO Lihua2,Maria Troulis3   

  1. 1.School of Dentistry, University of Queensland, Brisbane 4006, Australia
    2.Institute of Stem Cells and Tissue Engineering, School of Stomatology, Wenzhou Medical University, Wenzhou 325035, China
    3.Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital and Harvard School of Dental Medicine, Boston 02114, USA
  • Received:2019-05-15 Revised:2019-07-12 Online:2020-01-20 Published:2020-01-17
  • Contact: Qingsong YE E-mail:qye4@mgh.harvard.edu

Abstract:

Stem cells are a class of undifferentiated cells with high self-renewal and rapid proliferative capabilities. Undercertain conditions, stem cells can induce differentiation into other tissue cells of the human body, such as skeletal muscle cells, cardiomyocytes, osteoblasts, and nerve-like cells. In recent years, with the development of tissue engineering and regenerative medicine, stem cells have been extensively used in various fields of regenerative medicine as optimal seeded cells; however, there are still some problems, such as the decreased cell survival rate and regenerative capacity after transplantation, immune rejection, and ethical supervision. Therefore, it is difficult to universally and safely use stem cell banks for regeneration applications. The paracrine effect of stem cells has been extensively studied since its discovery. Increasing evidence supports the view that stem cells act in paracrine manner, and the secretion of exosomes plays a vital role in their biological functions. Exosomes are nanoscale extracellular vesicles containing biologically active molecules such as RNA and proteins; they possess similar functions to stem cells and play important roles in cell communication, immune response, and repair of tissue damage. At present, clinical studies on stem cell exosomes in tissue engineering and regenerative medicine have also been carried out in the fields of bone and cartilage repair, nerve tissue regeneration, liver tissue regeneration, skeletal muscle tissue engineering, vascular regeneration, taste bud repair, tooth regeneration, etc. In this paper, the composition, formation, release and identification of exosomes are introduced in detail. The research status of exosomes from different stem cell sources in tissue engineering and regenerative medicine is described, and their broad application prospects are discussed.

Key words: stem cells, exosomes, extracelluar vesicles, tissue engineering, regenerative medicine, bone regeneration, cartilage regeneration, tooth regeneration, angiogenesis, preclinical study

CLC Number: 

  • R78
[1] Lamichhane TN, Sonja S, Schardt JS , et al. Emerging roles for extracellular vesicles in tissue engineering and regenerative medicine[J]. Tissue Eng Part B Rev, 2015,21(1):45-54.
[2] Marote A, Teixeira FG, Mendes-Pinheiro B , et al. MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential[J]. Front Pharmacol, 2016,7:231.
[3] Greening DW, Gopal SK, Xu R , et al. Exosomes and their roles in immune regulation and cancer[J]. Semin Cell Dev Biol, 2015,40:72-81.
[4] Teng Y, Ren Y, Hu X , et al. MVP-mediated exosomal sorting of miR-193a promotes colon cancer progression[J]. Nat Commun, 2017,8:14448.
[5] Min H, Sun XD, Yang X , et al. Exosomes derived from irradiated esophageal carcinoma-infiltrating T cells promote metastasis by inducing the epithelial-mesenchymal transition in esophageal cancer cells[J]. Pathol Oncol Res, 2018,24(1):11-18.
[6] Pashoutan SD, Shamsasenjan K, Akbarzadehlaleh P . Mesenchymal stem cell-derived exosomes: new opportunity in cell-free therapy[J]. Adv Pharm Bull, 2016,6(3):293-299.
[7] Collino F, Pomatto M, Bruno S , et al. Exosome and microvesicle-enriched fractions isolated from mesenchymal stem cells by gradient separation showed different molecular signatures and functions on renal tubular epithelial cells[J]. Stem Cell Rev, 2017,13(2):226-243.
[8] Park S, Choi Y, Jung N , et al. Myogenic differentiation potential of human tonsil-derivedmesenchymal stem cells and their potential for use to promote skeletal muscle regeneration[J]. Int J Mol Med, 2016,37(5):1209-1220.
[9] Merino A, Ripoll E, De RL , et al. The timing of immunomodulation induced by mesenchymalstromal cells determines the outcome of the graft in experimental renal allotransplantation[J]. Cell Transplant, 2017,26(6):1017-1030.
[10] Jalalian SH, Ramezani M, Jalalian SA , et al. Exosomes, new biomarkers in early cancer detection[J]. AnalBiochem, 2019,571:1-13.
[11] Lai X, Wang M McElyea SD , et al. A microRNA Signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer[J]. Cancer Lett, 2017,393:86-93.
[12] Cheng WC, Liao TT, Lin CC , et al. RAB27B-activated secretion of stem-like tumor exosomes delivers the biomarker microrna-146a-5p, which promotes tumorigenesis and associates with an immunosuppressive tumor microenvironment in colorectal cancer[J]. Int J Cancer, 2019,145(8):2209-2224.
[13] Cui Y, Xu HF, Liu MY , et al. Mechanism of exosomal microRNA-224 in development of hepatocellular carcinoma and its diagnostic and prognostic value[J]. World J Gastroenterol, 2019,25(15):1890-1898.
[14] Hunsaker M, Barba G, Kingsley K , et al. Differential microRNA expression of miR-21 and miR-155 within oral cancer extracellular vesicles in response to melatonin[J]. Dent J, 2019,7(2):48.
[15] Lu M, Yuan S, Li S , et al. The exosome-derived biomarker in atherosclerosis and its clinical application[J]. J Cardiovasc Transl Res, 2019,12(1):68-74.
[16] Hosseinpour S, He Y, Nanda A , et al. MicroRNAs involved in the regulation of angiogenesis in bone regeneration[J]. Calcif Tissue Int, 2019,105(3):223-228.
[17] Colombo M, Raposo G, Thery C . Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles[J]. Annu Rev Cell Dev Biol, 2014,30:255-289.
[18] Egea-Jimenez AL, Zimmermann P . Lipids in exosome biology[J]. Handb Exp Pharmacol, 2019, doi: 10.1007/164_2019_220.
[19] Adamiak M, Sahoo S . Exosomes in myocardial repair: advances and challenges in the development of next-generation therapeutics[J]. Mol Ther, 2018,26(7):1635-1643.
[20] Oskouie MN, Moghaddam ANS, Butler AE , et al. Therapeutic use of curcumin-encapsulated and curcumin-primed exosomes[J]. J Cell Physiol, 2019,234(6):8182-8191.
[21] Ottaviani L, Windt LJD, Martins PADC . Exosomes: scytales in the damaged heart[J]. Ann Transl Med, 2016,4(11):222.
[22] Frydrychowicz M, Kolecka-Bednarczyk A, Madejczyk M , et al. Exosomes-- structure, biogenesis and biological role in non-small-cell lung cancer[J]. Scand J Immunol, 2015,81(1):2-10.
[23] Domenyuk V, Zhong Z, Stark A , et al. Plasma exosome profiling of cancer patients by a next generation systems biology approach[J]. Sci Rep, 2017,7(1):42741.
[24] Becker A, Thakur BK, Weiss JM , et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis[J]. Cancer Cell, 2016,30(6):836-848.
[25] Mulcahy LA, Pink RC, Carter DRF . Routes and mechanisms of extracellular vesicle uptake[J]. J Extracell Vesicles, 2014,3(1):24641.
[26] Yuan Y, Du W, Liu J , et al. Stem cell-derived exosome in cardiovascular diseases: macro roles of micro particles[J]. Front Pharmacol, 2018,9:547.
[27] Wunsch BH, Smith JT, Gifford SM , et al. Nanoscale lateral displacement arrays for the separation of exosomes and colloids down to 20 nm[J]. Nat Nanotechnol, 2016,11(11):936-940.
[28] Smith JT, Wunsch BH, Dogra N , et al. Integrated nanoscale deterministic lateral displacement arrays for separation of extracellular vesicles from clinically-relevant volumes of biological samples[J]. Lab Chip, 2018,18(24):3913-3925.
[29] Rider MA, Hurwitz SN, Meckes DG . Extra PEG: a polyethylene glycol-based method for enrichment of extracellular vesicles[J]. Sci Rep, 2016,6:23978.
[30] Li I, Nabet BY . Exosomes in the tumor microenvironment as mediators of cancer therapy resistance[J]. Mol Cancer, 2019,18(1):32.
[31] Dragovic RA, Collett GP, 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.
[32] Street JM, Barran PE, Mackay CL , et al. Identification and proteomic profiling of exosomes in human cerebrospinal fluid[J]. J Transl Med, 2012,10:5.
[33] Vader P, Mol EA, Pasterkamp G , et al. Extracellular vesicles for drug delivery[J]. Adv Drug Deliv Rev, 2016,106(PtA):148-156.
[34] Sun DM, Zhuang XY, Xiang XY , et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes[J]. Mol Ther, 2010,18(9):1606-1614.
[35] Zhang S, Chu WC, Lai RC , et al. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration[J]. Osteoarthr Cartil, 2016,24(12):2135-2140.
[36] Zhang S, Chuah SJ, Lai RC , et al. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity[J]. Biomaterials, 2018,156:16-27.
[37] Furuta T, Miyaki S, Ishitobi H , et al. Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model[J]. Stem Cells Transl Med, 2016,5(12):1620-1630.
[38] Zhang J, Liu X, Li H , et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway[J]. Stem Cell Res Ther, 2016,7(1):136.
[39] Jia Y, Zhu Y, Qiu S , et al. Exosomes secreted by endothelial progenitor cells accelerate bone regeneration during distraction osteogenesis by stimulating angiogenesis[J]. Stem Cell Res Ther. 2019,10(1):12.
[40] Hu L, Wang J, Zhou X , et al. Exosomes derived from human adipose mesenchymal stem cells accelerates cutaneous wound healing via optimizing the characteristics of fibroblasts[J]. Sci Rep, 2016,6:32993.
[41] Shi Q, Qian Z, Liu D , et al. GMSC-derived exosomes combined with a chitosan/silk hydrogel sponge accelerates wound healing in a diabetic rat skin defect model[J]. Front Physiol, 2017,8:904.
[42] Shabbir A, Cox A, Rodriguez-Menocal L , et al. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro[J]. Stem Cells Dev, 2015,24(14):1635-1647.
[43] Han-Soo K, Do-Young C, So Jeong Y , et al. Proteomic analysis of microvesicles derived from human mesenchymal stem cells[J]. J Proteome Res, 2012,11(2):839-849.
[44] Chen TS, RC Lai, Lee MM , et al. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs[J]. Nucleic Acids Res, 2010,38(1):215-224.
[45] Anderson JD, Johansson HJ, Graham CS , et al. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-Kappa b signaling[J]. Stem Cells, 2016,34(3):601-613.
[46] Baglio SR, Rooijers K, Koppers-Lalic D , et al. Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species[J]. Stem Cell Res Ther, 2015,6(1):127.
[47] Zhang Y, Shi S, Xu Q , et al. SIS-ECM laden with GMSC-derived exosomes promote taste bud regeneration[J]. J Dent Res, 2019,98(2):225-233.
[48] Xiao TT, Zhang WW, Jiao B , et al. The role of exosomes in the pathogenesis of Alzheimer′ disease[J]. Transl Neurodegener, 2017,6:3.
[49] Jarmalavičiūt$\dot{e}$ A, Tunaitis V, Pivoraite U , et al. Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis[J]. Cytotherapy, 2015,17(7):932-939.
[50] Zhang Y, Chopp M, Zheng GZ , et al. Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury[J]. Neurochem Int, 2017,111:69-81.
[51] Goncalves MB, Tony M, Earl C , et al. Neuronal RAR β signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration[J]. J Neurosci, 2015,35(47):15731-15745.
[52] Otero-Ortega L, Laso-Garcia F, Gomez-de Frutos M , et al. Role of exosomes as a treatment and potential biomarker for stroke[J]. Transl Stroke Res, 2019,10(3):241-249.
[53] Jiang N, Xiang LS, He L , et al. Exosomes mediate epithelium-mesenchyme crosstalk in organ development[J]. Acs Nano, 2017,11(8):7736-7746.
[54] Li Y, Wang XX, Ren JL , et al. Mandible exosomal ssc-miR-133b regulates tooth development in miniature swine via endogenous apoptosis[J]. Bone Res, 2018,6(1):28.
[55] Hu XL, Zhang YQ, Kong YY , et al. Lineage-specific exosomes promote the odontogenic differentiation of humandental pulp stem cells (DPSCs) through TGFβ1/Smads signaling pathway via transfer of microRNAs[J]. Stem Cell Res Ther, 2019,10(1):170.
[56] Huang CC, Narayanan R, Alapati S , et al. Exosomes as biomimetic tools for stem cell differentiation: applications in dental pulp tissue regeneration[J]. Biomaterials, 2016,111:103-115.
[57] Xian X, Gong Q, Li C , et al. Exosomes with highly angiogenic potential for possible use in pulp regeneration[J]. J Endod, 2018,44(5):751-758.
[58] Yoshihiro N, Shigeru M, Hiroyuki I , et al. Mesenchymal-stem-cell-derived exosomes accelerate skeletal muscle regeneration[J]. FEBS Lett, 2015,589(11):1257-1265.
[59] Wang K, Jiang Z, Webster KA , et al. Enhanced cardioprotection by human endometrium mesenchymal stem cells driven by exosomal MicroRNA-21[J]. Stem Cells Transl Med, 2017,6(1):209-222.
[60] Bian S, Zhang L, Duan L , et al. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model[J]. J Mol Med, 2014,92(4):387-397.
[61] Zhang Z, Yang J, Yan W , et al. Pretreatment of cardiac stem cells with exosomes derived from mesenchymal stem cells enhances myocardial repair[J]. J Am Heart Assoc, 2016,5(1):e002856.
[62] Tan CY, Lai RC, Wong W , et al. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models[J]. Stem Cell Res Ther, 2014,5(3):76.
[63] Damania A, Jaiman D, Teotia AK , et al. Mesenchymal stromal cell-derived exosome-rich fractionated secretome confers a hepatoprotective effect in liver injury[J]. Stem Cell Res Ther, 2018,9(1):31.
[64] Li T, Yan Y, Wang B , et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis[J]. Stem Cells Dev, 2013,22(6):845-854.
[65] Zhou Y, Xu H, Xu W , et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro[J]. Stem Cell Res Ther, 2013,4(2):34.
[66] van Koppen A, Joles JA, van Balkom BWM , et al. Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease[J]. Plos One, 2012,7(6):e38746.
[67] Li JW, Wei L, Han Z , et al. Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21-5p[J]. Eur J Pharmacol, 2019,852:68-76.
[68] Phinney DG, Di Giuseppe M, Njah J , et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs[J]. Nat Commun, 2015,6:8472.
[69] Toh WS, Zhang B, Lai RC , et al. Immune regulatory targets of mesenchymal stromal cell exosomes/small extracellular vesicles in tissue regeneration[J]. Cytotherapy, 2018,20(12):1419-1426.
[70] Sung BH, Ketova T, Hoshino D , et al. Directional cell movement through tissues is controlled by exosome secretion[J]. Nat Commun, 2015,6:7164.
[71] Cabral J, Ryan AE, Griffin MD , et al. Extracellular vesicles as modulators of wound healing[J]. Adv Drug Deliv Rev, 2018,129:394-406.
[72] NIH. Clinical Trials[Z/OL]. 2019. .
[73] NIH. Clinical Trials[Z/OL]. 2017. .
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