Browse > Article
http://dx.doi.org/10.15324/kjcls.2018.50.4.391

Mesenchymal Stem Cell-derived Exosomes: Applications in Cell-free Therapy  

Heo, June Seok (Department of Integrated Biomedical and Life Sciences, Graduate School, Korea University)
Kim, Jinkwan (Department of Biomedical Laboratory Science, College of Health Science, Jungwon University)
Publication Information
Korean Journal of Clinical Laboratory Science / v.50, no.4, 2018 , pp. 391-398 More about this Journal
Abstract
Mesenchymal stem cells (MSCs) are an attractive resource for refractory patients because of their anti-inflammatory/immunomodulatory capability and multi-lineage differentiation potential. The transplantation of MSCs has led to positive results in preclinical and clinical application to various diseases, including autoimmune disease, cardiovascular disease, cancer, liver cirrhosis, and ischemic stroke. On the other hand, studies have shown that paracrine factors, not direct cell replacement for damaged cells or tissue, are the main contributors in MSC-based therapy. More recently, evidence has indicated that MSC-derived exosomes play crucial roles in regulating the paracrine factors that can mediate tissue regeneration via transferring nucleic acids, proteins, and lipids to the local microenvironment and cell-to-cell communication. The use of these exosomes is likely to be beneficial for the therapeutic application of MSCs because their use can avoid harmful effects, such as tumor formation involved in cell transplantation. Therefore, therapeutic applications using MSC-derived exosomes might be safe and efficient strategies for regenerative medicine and tissue engineering. This review summarizes the recent advances and provides a comprehensive understanding of the role of MSC-derived exosomes as a therapeutic agent.
Keywords
Exosome; Mesenchymal stem cell; Stem cell; Therapy;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Dioufa N, Clark AM, Ma B, Beckwitt CH, Wells A. Bi-directional exosome-driven intercommunication between the hepatic niche and cancer cells. Mol Cancer. 2017;16:172.   DOI
2 Furlani D, Ugurlucan M, Ong L, Bieback K, Pittermann E, Westien I, et al. Is the intravascular administration of mesenchymal stem cells safe? Mesenchymal stem cells and intravital microscopy. Microvasc Res. 2009;77:370-376.   DOI
3 Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007;110:1362-1369.   DOI
4 Mathivanan S, Simpson RJ. ExoCarta: a compendium of exosomal proteins and RNA. Proteomics. 2009;9:4997-5000.   DOI
5 Chen TS, Lai RC, Lee MM, Choo AB, Lee CN, Lim SK. Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res. 2010;38:215-224.   DOI
6 Feng Y, Huang W, Wani M, Yu X, Asharf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One. 2014;9:e88685.   DOI
7 Katakowski M, Buller B, Zheng X, Lu Y, Rogers T, Osobamiro O, et al. Exosomes from marrow stromal cells expressing miR- 146b inhibit glioma growth. Cancer Lett. 2013;335:201-204.   DOI
8 Xin H, Li Y, Liu Z, Wang X, Shang X, Cui Y, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31:2737-2746.   DOI
9 Amarnath S, Foley JE, Farthing DE, Gress RE, Laurence A, Eckhaus MA, et al. Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo. Stem Cells. 2015;33:1200-1212.   DOI
10 Toma C, Wagner WR, Bowry S, Schwartz A, Villanueva F. Fate of culture-expanded mesenchymal stem cells in the microvasculature: in vivo observations of cell kinetics. Circ Res. 2009;104:398-402.   DOI
11 Yu B, Zhang X, Li X. Exosomes derived from mesenchymal stem cells. Int J Mol Sci. 2014;15:4142-4157.   DOI
12 Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28:970-973.   DOI
13 Zhang B, Yin Y, Lai RC, Tan SS, Choo AB, Lim SK. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014;23:1233-1244.   DOI
14 Cho BS, Kim JO, Ha DH, Yi YW. Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. Stem Cells Res Ther. 2018;9:187.   DOI
15 Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16:381-390.
16 Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood. 2001;98:2396-2402.   DOI
17 In't Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C, Kruisselbrink AB, van Benzooijen RL, et al. Mesenchymal stem cells in human second-trimester bone marrow, liver, lung, and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential. Haematologica. 2003;88:845-852.
18 Haynesworth SE, Baber MA, Caplan AI. Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone. 1992;13:69-80.   DOI
19 Bai L, Shao H, Wang H, Zhang Z, Su C, Dong L, et al. Effects of mesenchymal stem cell-derived exosomes on experimental autoimmune uveitis. Sci Rep. 2017;7:4323.   DOI
20 Zhang B, Yin Y, Lai RC, Lim SK. Immunotherapeutic potential of extracellular vesicles. Front Immunol. 2014;5:518.
21 Cosenza S, Toupet K, Maumus M, Luz-crawford P, Blanc-Brude O, Jorgensen C, et al. Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 2018;8:1399-1410.   DOI
22 Feng Y, Huang W, Wani M, Yu X, Asharf M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One. 2014;9:e88685.   DOI
23 Shao L, Zhang Y, Lan B, Wang J, Zhang Z, Zhang L, et al. MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. Biomed Res Int. 2017;2017:4150705.
24 Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med. 2014;92:387-397.   DOI
25 Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem. 2015;37:2415-2424.   DOI
26 Zhang Z, Yang J, Yan W, Li Y, Shen Z, Asahara T. Pretreatment of cardiac stem cells with exosomes derived from mesenchymal stem cells enhances myocardial repair. J Am Heart Assoc. 2016;5:e002856.
27 Shigemoto-Kuroda T, Oh JY, Kim DK, Jeong HJ, Park SY, Lee HJ, et al. MSC-derived extracellular vesicles attenuate immune responses in two autoimmune murine models: type 1 diabetes and uveoretinitis. Stem Cell Reports. 2017;8:1214-1225.   DOI
28 Subramanian K, Geraerts M, Pauwelyn KA, Park Y, Owens DJ, Muijtjens M, et al. Isolation procedure and characterization of multipotent adult progenitor cells from rat bone marrow. Methods Mol Biol. 2010;636:55-78.
29 Le Blanc K, Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005;11:321-334.   DOI
30 Majumdar MK, Thiede MA, Haynesworth SE, Bruder SP, Gerson SL. Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages. J Hematother Stem Cell Res. 2000;9:841-848.   DOI
31 Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood. 2005;105:4120-4126.   DOI
32 Rombouts WJ, Ploemacher RE. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia. 2003;17:160-170.   DOI
33 Cilloni D, Carlo-Stella C, Falzetti F, Sammarelli G, Regazzi E, Colla S, et al. Limited engraftment capacity of bone marrow-derived mesenchymal cells following T-cell-depleted hematopoietic stem cell transplantation. Blood. 2000;96:3637-3643.
34 Ko SF, Yip HK, Zhen YY, Lee CC, Lee CC, Huang CC, et al. Adipose-derived mesenchymal stem cell exosomes suppress hepatocellular carcinoma growth in a rat model: apparent diffusion coefficient, natural killer T-cell responses, and histopathological features. Stem Cells Int. 2015;2015:853506.
35 Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan Al. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16:557-564.
36 Wang S, Qu X, Zhao RC. Clinical applications of mesenchymal stem cells. J Hematol Oncol. 2012;5:19.   DOI
37 Wang Y, Wang S, Wu J, Jiang Y, Zhang H, Li S, et al. Hepatitis E virus infection in acute non-traumatic neurophathy: a large prospective case-control study in China. EBioMedicine. 2018;36:122-130. https://doi.org/10.1016/j.ebiom.2018.08.053.   DOI
38 Fiore EJ, Mazzolini G, Aquino JB. Mesenchymal stem/stromal cells in liver fibrosis: recent findings, old/new caveats and future perspectives. Stem Cell Rev. 2015;11:586-597.   DOI
39 Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 2014;5:76.   DOI
40 Hyun J, Wang S, Kim J, Kim GJ, Jung Y. MicroRNA125b-medicated hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells. Sci Rep. 2015;5:14135.   DOI
41 Thery C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;3:22.
42 Jung J, Choi JH, Lee Y, Park JW, Oh IH, Hwang SG, et al. Human placenta-derived mesenchymal stem cells promote hepatic regeneration in CCl4-injured rat liver model via increased autophagic mechanism. Stem Cells. 2013;31:1584-1596.   DOI
43 Jeong H, Yim HW, Park HJ, Cho Y, Hong H, Kim NJ, et al. Mesenchymal stem cell therapy for ischemic heart disease: systematic review and meta-analysis. Int J Stem Cells. 2018;11:1-12.   DOI
44 Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 1983;97:329-339.   DOI
45 Kahlert C, Melo SA, Protopopoy A, Tang J, Seth S, Koch M, et al. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem. 2014;289:3869-3875.   DOI
46 Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, The BJ, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65:336-341.   DOI
47 Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE, Gould SJ. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol. 2006;172:923-935.   DOI
48 Lai RC, Chen TS, Lim SK. Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen Med. 2011,6:481-492.   DOI
49 Nooshabadi VT, Mardpour S, Yousefi-Ahmadipour A, Allahverdi A, Izadpanah M, Daneshimehr F, et al. The extracellular vesicles-derived from mesenchymal stromal cells: a new therapeutic option in regenerative medicine. J Cell Biochem. 2018;119:8048-8073. https://doi.org/10.1002/jcb.26726.   DOI
50 Heo JS. Chondrogenic differentiation of human mesenchymal stem cells on a patterned polymer surface. Korean J Clin Lab Sci. 2015;47:117-124.   DOI
51 Wang LT, Ting CH, Yen ML, Liu KJ, Sytwu HK, Wu KK, et al. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci. 2016;23:76.   DOI
52 Lee PH, Lee JE, Kim HS, Song SK, Lee HS, Nam HS, et al. A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann Neurol. 2012;72:32-40.   DOI
53 Hodgkinson CP, Bareja A, Gomez JA, Dzau VJ. Emerging concepts in paracrine mechanisms in regenerative cardiovascular medicine and biology. Circ Res. 2016;118:95-107.   DOI