Int J Stem Cells.  2020 Mar;13(1):13-23. 10.15283/ijsc19108.

Mesenchymal Stem Cell-Derived Exosomes: A Promising Therapeutic Ace Card to Address Autoimmune Diseases

• Baharlooi
• Azimi M
• Salehi Z
• Izad M

• KMID: 2500563
• DOI: http://doi.org/10.15283/ijsc19108

Abstract

With the development of novel treatments for autoimmune disorders, it has become a popular research focus which mesenchymal stem cells (MSCs) have the capacity to counteract with autoimmune diseases progression. One of the underlying mechanisms behind their activities is the release of extracellular vesicles especially exosomes. MSC-derived exosomes are hypoimmunogenic nanocarriers which contain numerous immunoregulatory factors and similar to other exosomes, are able to pass through boundaries like the blood-brain barrier (BBB). Accumulating evidence provided by animal studies has demonstrated that MSC-derived exosomes, as a novel therapy, can re-induce self-tolerance, without subsequent complications reported for other treatments. Therefore, therapeutic applications of MSC-derived exosomes are contributing to core advances in the field of autoimmune diseases. Here, we briefly describe the biological characteristics of MSC-derived exosomes and review the experimentally verified outcomes for autoimmune disease therapy purposes.

Keyword

Mesenchymal stem cell; Exosome; Therapeutics; Immunomodulation; Autoimmune diseases

Reference

References

1. Crisan M, Corselli M, Chen CW, Péault B. 2011; Multilineage stem cells in the adult: a perivascular legacy? Organogenesis. 7:101–104. DOI: 10.4161/org.7.2.16150. PMID: 21593599. PMCID: PMC3142446.

2. Friedenstein AJ, Chailakhjan RK, Lalykina KS. 1970; The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3:393–403. DOI: 10.1111/j.1365-2184.1970.tb00347.x. PMID: 5523063.

3. Murray IR, West CC, Hardy WR, James AW, Park TS, Nguyen A, Tawonsawatruk T, Lazzari L, Soo C, Péault B. 2014; Natural history of mesenchymal stem cells, from vessel walls to culture vessels. Cell Mol Life Sci. 71:1353–1374. DOI: 10.1007/s00018-013-1462-6. PMID: 24158496.

4. Hassan G, Kasem I, Soukkarieh C, Aljamali M. 2017; A Simple method to isolate and expand human umbilical cord derived mesenchymal stem cells: using explant method and umbilical cord blood serum. Int J Stem Cells. 10:184–192. DOI: 10.15283/ijsc17028. PMID: 28844128. PMCID: PMC5741200.

5. Caplan AI. 2008; All MSCs are pericytes? Cell Stem Cell. 3:229–230. DOI: 10.1016/j.stem.2008.08.008. PMID: 18786406.

6. Pham H, Tonai R, Wu M, Birtolo C, Chen M. 2018; CD73, CD90, CD105 and Cadherin-11 RT-PCR screening for mesenchymal stem cells from cryopreserved human cord tissue. Int J Stem Cells. 11:26–38. DOI: 10.15283/ijsc17015. PMID: 29843192. PMCID: PMC5984056.

7. Geevarghese A, Herman IM. 2014; Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies. Transl Res. 163:296–306. DOI: 10.1016/j.trsl.2014.01.011. PMID: 24530608. PMCID: PMC3976718.

8. Guimarães-Camboa N, Cattaneo P, Sun Y, Moore-Morris T, Gu Y, Dalton ND, Rockenstein E, Masliah E, Peterson KL, Stallcup WB, Chen J, Evans SM. 2017; Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell. 20:345–359.e5. DOI: 10.1016/j.stem.2016.12.006. PMID: 28111199. PMCID: PMC5337131.

9. Caplan AI. 2010; What's in a name? Tissue Eng Part A. 16:2415–2417. DOI: 10.1089/ten.tea.2010.0216. PMID: 20412005.

10. Caplan AI. 2017; Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 6:1445–1451. DOI: 10.1002/sctm.17-0051. PMID: 28452204. PMCID: PMC5689741.

11. Bernardo ME, Fibbe WE. 2013; Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 13:392–402. DOI: 10.1016/j.stem.2013.09.006. PMID: 24094322.

12. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM. 2002; Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 99:3838–3843. DOI: 10.1182/blood.V99.10.3838. PMID: 11986244.

13. Bruno S, Deregibus MC, Camussi G. 2015; The secretome of mesenchymal stromal cells: role of extracellular vesicles in immunomodulation. Immunol Lett. 168:154–158. DOI: 10.1016/j.imlet.2015.06.007. PMID: 26086886.

14. Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, Kyurkchiev S. 2014; Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 6:552–570. DOI: 10.4252/wjsc.v6.i5.552. PMID: 25426252. PMCID: PMC4178255.

15. Edgar JR, Eden ER, Futter CE. 2014; Hrs- and CD63-dependent competing mechanisms make different sized endosomal intraluminal vesicles. Traffic. 15:197–211. DOI: 10.1111/tra.12139. PMID: 24279430. PMCID: PMC4253088.

16. Bobrie A, Colombo M, Krumeich S, Raposo G, Théry C. 2012; Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation. J Extracell Vesicles. 1:18397. DOI: 10.3402/jev.v1i0.18397. PMID: 24009879. PMCID: PMC3760636.

17. Théry C, Boussac M, Véron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S. 2001; Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol. 166:7309–7318. DOI: 10.4049/jimmunol.166.12.7309. PMID: 11390481.

18. Cocucci E, Meldolesi J. 2015; Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 25:364–372. DOI: 10.1016/j.tcb.2015.01.004. PMID: 25683921.

19. Akers JC, Gonda D, Kim R, Carter BS, Chen CC. 2013; Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 113:1–11. DOI: 10.1007/s11060-013-1084-8. PMID: 23456661. PMCID: PMC5533094.

20. Hess C, Sadallah S, Hefti A, Landmann R, Schifferli JA. 1999; Ectosomes released by human neutrophils are specialized functional units. J Immunol. 163:4564–4573.

21. Johnstone RM. 1992; The Jeanne Manery-Fisher memorial lecture 1991. Maturation of reticulocytes: formation of exosomes as a mechanism for shedding membrane proteins. Biochem Cell Biol. 70:179–190. DOI: 10.1139/o92-028. PMID: 1515120.

22. Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K. 2006; Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 103:11172–11177. DOI: 10.1073/pnas.0603838103. PMID: 16837572. PMCID: PMC1544060.

23. Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G. 2004; Cells release prions in association with exosomes. Proc Natl Acad Sci U S A. 101:9683–9688. DOI: 10.1073/pnas.0308413101. PMID: 15210972. PMCID: PMC470735.

24. Emmanouilidou E, Melachroinou K, Roumeliotis T, Garbis SD, Ntzouni M, Margaritis LH, Stefanis L, Vekrellis K. 2010; Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J Neurosci. 30:6838–6851. DOI: 10.1523/JNEUROSCI.5699-09.2010. PMID: 20484626. PMCID: PMC3842464.

25. Gomes C, Keller S, Altevogt P, Costa J. 2007; Evidence for secretion of Cu,Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis. Neurosci Lett. 428:43–46. DOI: 10.1016/j.neulet.2007.09.024. PMID: 17942226.

26. Tamai K, Tanaka N, Nakano T, Kakazu E, Kondo Y, Inoue J, Shiina M, Fukushima K, Hoshino T, Sano K, Ueno Y, Shimosegawa T, Sugamura K. 2010; Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. Biochem Biophys Res Commun. 399:384–390. DOI: 10.1016/j.bbrc.2010.07.083. PMID: 20673754.

27. Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, Patel T, Piroyan A, Sokolsky M, Kabanov AV, Batrakova EV. 2015; Exosomes as drug delivery vehicles for Parkinson's disease therapy. J Control Release. 207:18–30. DOI: 10.1016/j.jconrel.2015.03.033. PMID: 25836593. PMCID: PMC4430381.

28. Blanchard N, Lankar D, Faure F, Regnault A, Dumont C, Raposo G, Hivroz C. 2002; TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/zeta complex. J Immunol. 168:3235–3241. DOI: 10.4049/jimmunol.168.7.3235. PMID: 11907077.

29. Buschow SI, Nolte-'t Hoen EN, van Niel G, Pols MS, ten Broeke T, Lauwen M, Ossendorp F, Melief CJ, Raposo G, Wubbolts R, Wauben MH, Stoorvogel W. 2009; MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic. 10:1528–1542. DOI: 10.1111/j.1600-0854.2009.00963.x. PMID: 19682328.

30. Lo Sicco C, Reverberi D, Balbi C, Ulivi V, Principi E, Pascucci L, Becherini P, Bosco MC, Varesio L, Franzin C, Pozzobon M, Cancedda R, Tasso R. 2017; Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 6:1018–1028. DOI: 10.1002/sctm.16-0363. PMID: 28186708. PMCID: PMC5442783.

31. Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, Zhao Y, Liu H, Fu X, Han W. 2015; LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 13:308. DOI: 10.1186/s12967-015-0642-6. PMID: 26386558. PMCID: PMC4575470.

32. Bissig C, Gruenberg J. 2014; ALIX and the multivesicular endosome: ALIX in wonderland. Trends Cell Biol. 24:19–25. DOI: 10.1016/j.tcb.2013.10.009. PMID: 24287454.

33. Abrami L, Lindsay M, Parton RG, Leppla SH. , van der Goot FG. 2004; Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway. J Cell Biol. 166:645–651. DOI: 10.1083/jcb.200312072. PMID: 15337774. PMCID: PMC2172425.

34. Denzer K, van Eijk M, Kleijmeer MJ, Jakobson E, de Groot C, Geuze HJ. 2000; Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol. 165:1259–1265. DOI: 10.4049/jimmunol.165.3.1259. PMID: 10903724.

35. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW, Matthay MA. 2010; Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 28:2229–2238. DOI: 10.1002/stem.544. PMID: 20945332. PMCID: PMC3293245.

36. Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Pérez Lanzón M, Zini N, Naaijkens B, Perut F, Niessen HW, Baldini N, Pegtel DM. 2015; Human bone marrow- and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 6:127. DOI: 10.1186/s13287-015-0116-z. PMID: 26129847. PMCID: PMC4529699.

37. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L. 2006; Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood. 107:1484–1490. DOI: 10.1182/blood-2005-07-2775. PMID: 16239427.

38. Di Trapani M, Bassi G, Midolo M, Gatti A, Kamga PT, Cassaro A, Carusone R, Adamo A, Krampera M. 2016; Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Sci Rep. 6:24120. DOI: 10.1038/srep24120. PMID: 27071676. PMCID: PMC4829861.

39. Eirin A, Zhu XY, Puranik AS, Tang H, McGurren KA, van Wijnen AJ, Lerman A, Lerman LO. 2017; Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int. 92:114–124. DOI: 10.1016/j.kint.2016.12.023. PMID: 28242034. PMCID: PMC5483390.

40. Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. 2014; Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 5:76. DOI: 10.1186/scrt465. PMID: 24915963. PMCID: PMC4229780.

41. Okunishi K, Dohi M, Nakagome K, Tanaka R, Mizuno S, Matsumoto K, Miyazaki J, Nakamura T, Yamamoto K. 2005; A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. J Immunol. 175:4745–4753. DOI: 10.4049/jimmunol.175.7.4745. PMID: 16177122.

42. Garo LP, Murugaiyan G. 2016; Contribution of MicroRNAs to autoimmune diseases. Cell Mol Life Sci. 73:2041–2051. DOI: 10.1007/s00018-016-2167-4. PMID: 26943802.

43. Harding C, Heuser J, Stahl P. 1983; Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 97:329–339. DOI: 10.1083/jcb.97.2.329. PMID: 6309857. PMCID: PMC2112509.

44. Bigagli E, De Filippo C, Castagnini C, Toti S, Acquadro F, Giudici F, Fazi M, Dolara P, Messerini L, Tonelli F, Luceri C. 2016; DNA copy number alterations, gene expression changes and disease-free survival in patients with colorectal cancer: a 10 year follow-up. Cell Oncol. 39:545–558. DOI: 10.1007/s13402-016-0299-z. PMID: 27709558.

45. Liu Y, Lou G, Li A, Zhang T, Qi J, Ye D, Zheng M, Chen Z. 2018; AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages. EBioMedicine. 36:140–150. DOI: 10.1016/j.ebiom.2018.08.054. PMID: 30197023. PMCID: PMC6197728.

46. Ti D, Hao H, Fu X, Han W. 2016; Mesenchymal stem cells-derived exosomal microRNAs contribute to wound inflammation. Sci China Life Sci. 59:1305–1312. DOI: 10.1007/s11427-016-0240-4. PMID: 27864711.

47. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK. 2010; Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 4:214–222. DOI: 10.1016/j.scr.2009.12.003. PMID: 20138817.

48. Choi H, Lee DS. 2016; Illuminating the physiology of extracellular vesicles. Stem Cell Res Ther. 7:55. DOI: 10.1186/s13287-016-0316-1. PMID: 27084088. PMCID: PMC4833943.

49. Li SD, Huang L. 2009; Nanoparticles evading the reticuloendothelial system: role of the supported bilayer. Biochim Biophys Acta. 1788:2259–2266. DOI: 10.1016/j.bbamem.2009.06.022. PMID: 19595666. PMCID: PMC2757503.

50. Klyushnenkova E, Mosca JD, Zernetkina V, Majumdar MK, Beggs KJ, Simonetti DW, Deans RJ, McIntosh KR. 2005; T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci. 12:47–57. DOI: 10.1007/s11373-004-8183-7. PMID: 15864738.

51. Yeo RW, Lai RC, Zhang B, Tan SS, Yin Y, Teh BJ, Lim SK. 2013; Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 65:336–341. DOI: 10.1016/j.addr.2012.07.001. PMID: 22780955.

52. Ma ZJ, Wang YH, Li ZG, Wang Y, Li BY, Kang HY, Wu XY. 2019; Immunosuppressive effect of exosomes from mesenchymal stromal cells in defined medium on experimental colitis. Int J Stem Cells. doi: 10.15283/ijsc18139. [Epub ahead of print]. DOI: 10.15283/ijsc18139. PMID: 31242720. PMCID: PMC6881044.

53. Cosenza S, Toupet K, Maumus M, Luz-Crawford P, Blanc-Brude O, Jorgensen C, Noël D. 2018; Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis. Theranostics. 8:1399–1410. DOI: 10.7150/thno.21072. PMID: 29507629. PMCID: PMC5835945.

54. Grange C, Tapparo M, Bruno S, Chatterjee D, Quesenberry PJ, Tetta C, Camussi G. 2014; Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int J Mol Med. 33:1055–1063. DOI: 10.3892/ijmm.2014.1663. PMID: 24573178. PMCID: PMC4020482.

55. Meng F, Wang J, Ping Q, Yeo Y. 2018; Quantitative assessment of nanoparticle biodistribution by fluorescence imaging, revisited. ACS Nano. 12:6458–6468. DOI: 10.1021/acsnano.8b02881. PMID: 29920064. PMCID: PMC6105334.

56. Morishita M, Takahashi Y, Nishikawa M, Sano K, Kato K, Yamashita T, Imai T, Saji H, Takakura Y. 2015; Quantitative analysis of tissue distribution of the B16BL6-derived exosomes using a streptavidin-lactadherin fusion protein and iodine-125-labeled biotin derivative after intravenous injection in mice. J Pharm Sci. 104:705–713. DOI: 10.1002/jps.24251. PMID: 25393546.

57. Badr CE, Tannous BA. 2011; Bioluminescence imaging: progress and applications. Trends Biotechnol. 29:624–633. DOI: 10.1016/j.tibtech.2011.06.010. PMID: 21788092. PMCID: PMC4314955.

58. Geurts JJ, Barkhof F. 2008; Grey matter pathology in multiple sclerosis. Lancet Neurol. 7:841–851. DOI: 10.1016/S1474-4422(08)70191-1.

59. Popescu BF, Lucchinetti CF. 2012; Pathology of demyelinating diseases. Annu Rev Pathol. 7:185–217. DOI: 10.1146/annurev-pathol-011811-132443. PMID: 22313379.

60. Salehi Z, Doosti R, Beheshti M, Janzamin E, Sahraian MA, Izad M. 2016; Differential frequency of CD8＋ T cell subsets in multiple sclerosis patients with various clinical patterns. PLoS One. 11:e0159565. DOI: 10.1371/journal.pone.0159565. PMID: 27467597. PMCID: PMC4965085.

61. Tanasescu R, Ionete C, Chou IJ, Constantinescu CS. 2014; Advances in the treatment of relapsing-remitting multiple sclerosis. Biomed J. 37:41–49. DOI: 10.4103/2319-4170.130440. PMID: 24732658.

62. Gholamzad M, Ebtekar M, Ardestani MS, Azimi M, Mahmodi Z, Mousavi MJ, Aslani S. 2019; A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm Res. 68:25–38. DOI: 10.1007/s00011-018-1185-0. PMID: 30178100.

63. Nakhaei-Nejad M, Barilla D, Lee CH, Blevins G, Giuliani F. 2017; Characterization of lymphopenia in patients with MS treated with dimethyl fumarate and fingolimod. Neurol Neuroimmunol Neuroinflamm. 5:e432. DOI: 10.1212/NXI.0000000000000432. PMID: 29296636. PMCID: PMC5746425.

64. Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, Carra A, Elovaara I, Fazekas F, Hartung HP, Hillert J, King J, Komoly S, Lubetzki C, Montalban X, Myhr KM, Ravnborg M, Rieckmann P, Wynn D, Young C, Filippi M. PreCISe Study Group. 2009; Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 374:1503–1511. DOI: 10.1016/S0140-6736(09)61259-9.

65. Wang M, Yuan Q, Xie L. 2018; Mesenchymal stem cell-based immunomodulation: properties and clinical application. Stem Cells Int. 2018:3057624. DOI: 10.1155/2018/3057624. PMID: 30013600. PMCID: PMC6022321.

66. Emamnejad R, Sahraian M, Shakiba Y, Salehi Z, Masoomi A, Imani D, Najafi F, Laribi B, Shirzad H, Izad M. 2019; Circulating mesenchymal stem cells, stromal derived factor (SDF)-1 and IP-10 levels increased in clinically active multiple sclerosis patients but not in clinically stable patients treated with beta interferon. Mult Scler Relat Disord. 35:233–238. DOI: 10.1016/j.msard.2019.08.013. PMID: 31421626.

67. Sargent A, Shano G, Karl M, Garrison E, Miller C, Miller RH. 2018; Transcriptional profiling of mesenchymal stem cells identifies distinct neuroimmune pathways altered by CNS disease. Int J Stem Cells. 11:48–60. DOI: 10.15283/ijsc17062. PMID: 29699382. PMCID: PMC5984058.

68. Johnson TV, Bull ND, Hunt DP, Marina N, Tomarev SI, Martin KR. 2010; Neuroprotective effects of intravitreal mesenchymal stem cell transplantation in experimental glaucoma. Invest Ophthalmol Vis Sci. 51:2051–2059. DOI: 10.1167/iovs.09-4509. PMID: 19933193. PMCID: PMC2868400.

69. Herrero C, Pérez-Simón JA. 2010; Immunomodulatory effect of mesenchymal stem cells. Braz J Med Biol Res. 43:425–430. DOI: 10.1590/S0100-879X2010007500033. PMID: 20490429.

70. Nasri F, Mohtasebi MS, Hashemi E, Zarrabi M, Gholijani N, Sarvestani EK. 2018; Therapeutic efficacy of mesenchymal stem cells and mesenchymal stem cells-derived neural progenitors in experimental autoimmune encephalomyelitis. Int J Stem Cells. 11:68–77. DOI: 10.15283/ijsc17052. PMID: 29699380. PMCID: PMC5984060.

71. Marti LC, Ribeiro AA, Hamerschlak N. 2011; Immunomodulatory effect of mesenchymal stem cells. Einstein (Sao Paulo). 9:224–228. DOI: 10.1590/s1679-45082011rw1843. PMID: 26760821.

72. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, Ju S, Mu J, Zhang L, Steinman L, Miller D, Zhang HG. 2011; Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 19:1769–1779. DOI: 10.1038/mt.2011.164. PMID: 21915101. PMCID: PMC3188748.

73. Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA, Mardani K. 2012; Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling. Immunol Lett. 147(1-2):47–54. DOI: 10.1016/j.imlet.2012.06.001. PMID: 22705267.

74. Laso-García F, Ramos-Cejudo J, Carrillo-Salinas FJ, Otero-Ortega L, Feliú A, Gómez-de Frutos M, Mecha M, Díez-Tejedor E, Guaza C, Gutiérrez-Fernández M. 2018; Therapeutic potential of extracellular vesicles derived from human mesenchymal stem cells in a model of progressive multiple sclerosis. PLoS One. 13:e0202590. DOI: 10.1371/journal.pone.0202590. PMID: 30231069. PMCID: PMC6145506.

75. Li Z, Liu F, He X, Yang X, Shan F, Feng J. 2019; Exosomes derived from mesenchymal stem cells attenuate inflammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia. Int Immunopharmacol. 67:268–280. DOI: 10.1016/j.intimp.2018.12.001. PMID: 30572251.

76. Hosseini Shamili F, Alibolandi M, Rafatpanah H, Abnous K, Mahmoudi M, Kalantari M, Taghdisi SM, Ramezani M. 2019; Immunomodulatory properties of MSC-derived exosomes armed with high affinity aptamer toward mylein as a platform for reducing multiple sclerosis clinical score. J Control Release. 299:149–164. DOI: 10.1016/j.jconrel.2019.02.032. PMID: 30807806.

77. Malmström V, Catrina AI, Klareskog L. 2017; The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol. 17:60–75. DOI: 10.1038/nri.2016.124. PMID: 27916980.

78. McInnes IB, Schett G. 2017; Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 389:2328–2337. DOI: 10.1016/S0140-6736(17)31472-1.

79. Benjamin O, Lappin SL. 2019. Jan. Disease Modifying Anti-Rheumatic Drugs (DMARD). 2019 Oct 2. StatPearls [Internet]. StatPearls Publishing;Treasure Island: Available from: http://www.ncbi.nlm.nih.gov/books/NBK507863/. cited 2019 Jan 2.

80. Cosenza S, Ruiz M, Maumus M, Jorgensen C, Noël D. 2017; Pathogenic or therapeutic extracellular vesicles in rheumatic diseases: role of mesenchymal stem cell-derived vesicles. Int J Mol Sci. 18:E889. DOI: 10.3390/ijms18040889. PMID: 28441721. PMCID: PMC5412468.

81. Withrow J, Murphy C, Liu Y, Hunter M, Fulzele S, Hamrick MW. 2016; Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis. Arthritis Res Ther. 18:286. DOI: 10.1186/s13075-016-1178-8. PMID: 27906035. PMCID: PMC5134070.

82. Conforti A, Scarsella M, Starc N, Giorda E, Biagini S, Proia A, Carsetti R, Locatelli F, Bernardo ME. 2014; Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem Cells Dev. 23:2591–2599. DOI: 10.1089/scd.2014.0091. PMID: 24937591. PMCID: PMC4201301.

83. Chen Z, Wang H, Xia Y, Yan F, Lu Y. 2018; Therapeutic potential of mesenchymal cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF. J Immunol. 201:2472–2482. DOI: 10.4049/jimmunol.1800304. PMID: 30224512. PMCID: PMC6176104.

84. Gao J, Xu K, Zhang G, Han J, Liu Y, Zhang L. 2019; FRI0510 the effect and mechanism of human umbilical cord mesenchymal stem cells-derived exosomes on bone destruction of collagen induced arthritis rats. Ann Rheum Dis. 78:950. DOI: 10.1136/annrheumdis-2019-eular.7325.

85. He P. 2019; AB0291E the effect of human umbilical cord mesenchymal stem cells-derived exosomes on chemokines in collagen-induced arthritis rats. Ann Rheum Dis. 78:1606. DOI: 10.1136/annrheumdis-2019-eular.7165.

86. Bluestone JA, Herold K, Eisenbarth G. 2010; Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature. 464:1293–1300. DOI: 10.1038/nature08933. PMID: 20432533. PMCID: PMC4959889.

87. Cohen DJ, St Martin L, Christensen LL, Bloom RD, Sung RS. 2006; Kidney and pancreas transplantation in the United States, 1995-2004. Am J Transplant. 6:1153–1169. DOI: 10.1111/j.1600-6143.2006.01272.x. PMID: 16613593.

88. Gruessner AC, Sutherland DE. 2008; Pancreas transplant outcomes for United States (US) cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Clin Transpl. 45–56.

89. Johnson PR, Jones KE. 2012; Pancreatic islet transplantation. Semin Pediatr Surg. 21:272–280. DOI: 10.1053/j.sempedsurg.2012.05.012. PMID: 22800980.

90. Ballinger WF, Lacy PE. 1972; Transplantation of intact pancreatic islets in rats. Surgery. 72:175–186.

91. Chatenoud L, Primo J, Bach JF. 1997; CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J Immunol. 158:2947–2954.

92. Hirsch R, Gress RE, Pluznik DH, Eckhaus M, Bluestone JA. 1989; Effects of in vivo administration of anti-CD3 monoclonal antibody on T cell function in mice. II. In vivo activation of T cells. J Immunol. 142:737–743.

93. Ferran C, Dautry F, Mérite S, Sheehan K, Schreiber R, Grau G, Bach JF, Chatenoud L. 1994; Anti-tumor necrosis factor modulates anti-CD3-triggered T cell cytokine gene expression in vivo. J Clin Invest. 93:2189–2196. DOI: 10.1172/JCI117215. PMID: 8182150. PMCID: PMC294360.

94. Ezquer F, Ezquer M, Contador D, Ricca M, Simon V, Conget P. 2012; The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells. 30:1664–1674. DOI: 10.1002/stem.1132. PMID: 22644660.

95. Nakano M, Nagaishi K, Konari N, Saito Y, Chikenji T, Mizue Y, Fujimiya M. 2016; Bone marrow-derived mesenchymal stem cells improve diabetes-induced cognitive impairment by exosome transfer into damaged neurons and astrocytes. Sci Rep. 6:24805. DOI: 10.1038/srep24805. PMID: 27102354. PMCID: PMC4840335.

96. Wen D, Peng Y, Liu D, Weizmann Y, Mahato RI. 2016; Mesenchymal stem cell and derived exosome as small RNA carrier and Immunomodulator to improve islet transplantation. J Control Release. 238:166–175. DOI: 10.1016/j.jconrel.2016.07.044. PMID: 27475298.

97. Nojehdehi S, Soudi S, Hesampour A, Rasouli S, Soleimani M, Hashemi SM. 2018; Immunomodulatory effects of mesenchymal stem cell-derived exosomes on experimental type-1 autoimmune diabetes. J Cell Biochem. 119:9433–9443. DOI: 10.1002/jcb.27260. PMID: 30074271.

98. Rosenbaum JT. 2015; Nibbling away at the diagnosis of idiopathic uveitis. JAMA Ophthalmol. 133:146–147. DOI: 10.1001/jamaophthalmol.2014.4272. PMID: 25356928.

99. Yang P. 2015; Editorial: uveitis: pathology, molecular mechanisms and therapy. Curr Mol Med. 15:510. DOI: 10.2174/1566524015999150804104144. PMID: 26242392.

100. Rosenbaum JT. 2010; Future for biological therapy for uveitis. Curr Opin Ophthalmol. 21:473–477. DOI: 10.1097/ICU.0b013e32833f00b3. PMID: 20829688.

101. Zhang X, Ren X, Li G, Jiao C, Zhang L, Zhao S, Wang J, Han ZC, Li X. 2011; Mesenchymal stem cells ameliorate experimental autoimmune uveoretinitis by comprehensive modulation of systemic autoimmunity. Invest Ophthalmol Vis Sci. 52:3143–3152. DOI: 10.1167/iovs.10-6334. PMID: 21296818.

102. Tasso R, Ilengo C, Quarto R, Cancedda R, Caspi RR, Pennesi G. 2012; Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 53:786–793. DOI: 10.1167/iovs.11-8211. PMID: 22232435. PMCID: PMC3317420.

103. Li G, Yuan L, Ren X, Nian H, Zhang L, Han ZC, Li X, Zhang X. 2013; The effect of mesenchymal stem cells on dynamic changes of T cell subsets in experimental autoimmune uveoretinitis. Clin Exp Immunol. 173:28–37. DOI: 10.1111/cei.12080. PMID: 23607419. PMCID: PMC3694532.

104. Bai L, Shao H, Wang H, Zhang Z, Su C, Dong L, Yu B, Chen X, Li X, Zhang X. 2017; Effects of mesenchymal stem cell-derived exosomes on experimental autoimmune uveitis. Sci Rep. 7:4323. DOI: 10.1038/s41598-017-04559-y. PMID: 28659587. PMCID: PMC5489510.