Abstract
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into diverse cell lineages. MSC based therapy has become a widely experimented treatment strategy in regenerative medicine with promising outcomes. Recent reports suggest that much of the therapeutic effects of MSCs are mediated by their secretome that is expressed through extracellular vesicles (EVs). EVs are lipid bilayer bound components that carry cellular proteins, mRNA, lncRNAs, and other molecules in order to mediate intercellular communication and signaling. In fact, MSC-derived EVs have been observed to implement the same therapeutic effects as MSCs with minimal adverse effects and could be used as an alternative treatment method to MSC-based therapy. The regenerative activity of MSC-EVs has been observed in relation to multiple cell/tissue lineages using various animal models. However, further research and clinical trials are essential for the advancement of this novel treatment strategy. This review provides an insight into the available literature on applications of MSC-EVs in relation to angiogenesis, neurogenesis, hepatic and kidney regeneration, and wound healing.
Keywords: Extracellular vesicles, mesenchymal stem cells, regenerative medicine, secretome, paracrine signaling, regeneration.
[http://dx.doi.org/10.1073/pnas.1508520112] [PMID: 26598661]
[http://dx.doi.org/10.1590/1678-4324-2016150383]
[http://dx.doi.org/10.1111/j.1365-2591.2011.01990.x] [PMID: 22142405]
[http://dx.doi.org/10.1089/scd.2009.0446] [PMID: 20050811]
[http://dx.doi.org/10.1186/1472-6750-7-26] [PMID: 17537254]
[http://dx.doi.org/10.2460/ajvr.73.8.1305] [PMID: 22849692]
[http://dx.doi.org/10.1016/j.exphem.2005.07.003] [PMID: 16263424]
[http://dx.doi.org/10.1016/j.fertnstert.2010.08.035] [PMID: 20864098]
[http://dx.doi.org/10.1093/rheumatology/ken114] [PMID: 18390894]
[http://dx.doi.org/10.1038/oby.2003.11] [PMID: 12529487]
[http://dx.doi.org/10.1186/s13287-018-0942-x] [PMID: 30053888]
[http://dx.doi.org/10.1016/S2095-3119(13)60497-9]
[http://dx.doi.org/10.1007/978-1-60761-999-4_20] [PMID: 21431525]
[http://dx.doi.org/10.1080/14653240802716582] [PMID: 19253075]
[http://dx.doi.org/10.1002/hep.20469] [PMID: 15562440]
[http://dx.doi.org/10.1182/blood-2004-04-1559] [PMID: 15494428]
[http://dx.doi.org/10.1136/postgradmedj-2013-132387] [PMID: 25335795]
[http://dx.doi.org/10.1634/stemcells.2007-0637] [PMID: 17901396]
[http://dx.doi.org/10.1016/S1010-5182(02)00143-9] [PMID: 12553923]
[http://dx.doi.org/10.1016/j.biomaterials.2012.12.029] [PMID: 23332320]
[http://dx.doi.org/10.1016/j.jot.2017.03.002] [PMID: 29662796]
[http://dx.doi.org/10.1089/ten.2004.10.1818] [PMID: 15684690]
[http://dx.doi.org/10.1038/srep31306] [PMID: 27510321]
[http://dx.doi.org/10.1016/j.jacc.2007.07.041] [PMID: 17964040]
[http://dx.doi.org/10.1056/NEJMoa060186] [PMID: 16990384]
[http://dx.doi.org/10.1016/j.stem.2011.06.008] [PMID: 21726829]
[http://dx.doi.org/10.1096/fj.05-5211com] [PMID: 16581974]
[http://dx.doi.org/10.1016/j.stem.2009.05.003] [PMID: 19570514]
[http://dx.doi.org/10.1186/1479-5876-9-29] [PMID: 21418664]
[http://dx.doi.org/10.1634/stemcells.2006-0762] [PMID: 17363552]
[http://dx.doi.org/10.1038/sj.bmt.1705368] [PMID: 16604097]
[http://dx.doi.org/10.1016/j.cellimm.2017.07.010] [PMID: 28778535]
[http://dx.doi.org/10.1016/j.scr.2009.12.003] [PMID: 20138817]
[http://dx.doi.org/10.1371/journal.pone.0072604] [PMID: 23991127]
[http://dx.doi.org/10.3389/fcell.2020.00149] [PMID: 32226787]
[http://dx.doi.org/10.1038/ncomms1285] [PMID: 21505438]
[http://dx.doi.org/10.1371/journal.ppat.1004424] [PMID: 25275643]
[http://dx.doi.org/10.1634/stemcells.2004-0062] [PMID: 15579636]
[http://dx.doi.org/10.1002/stem.2087] [PMID: 26148841]
[http://dx.doi.org/10.1038/s41598-017-04559-y] [PMID: 28659587]
[http://dx.doi.org/10.1083/jcb.201211138] [PMID: 23420871]
[http://dx.doi.org/10.1146/annurev-cellbio-101512-122326] [PMID: 25288114]
[http://dx.doi.org/10.1111/j.1365-2141.1967.tb08741.x] [PMID: 6025241]
[http://dx.doi.org/10.1002/0471143030.cb0322s30] [PMID: 18228490]
[http://dx.doi.org/10.3402/jev.v4.29260] [PMID: 26563735]
[http://dx.doi.org/10.1113/JP272182] [PMID: 27104781]
[http://dx.doi.org/10.1016/S0014-5793(02)03406-3] [PMID: 12401199]
[PMID: 12414662]
[http://dx.doi.org/10.1074/jbc.273.32.20121] [PMID: 9685355]
[http://dx.doi.org/10.1002/pmic.201200329] [PMID: 23401200]
[http://dx.doi.org/10.1038/ncb1929] [PMID: 19684575]
[http://dx.doi.org/10.1073/pnas.0308413101] [PMID: 15210972]
[http://dx.doi.org/10.1038/nri2567] [PMID: 19498381]
[http://dx.doi.org/10.1038/nrm2755] [PMID: 19696797]
[http://dx.doi.org/10.1182/blood-2004-03-0824] [PMID: 15284116]
[http://dx.doi.org/10.1038/nrm.2017.125] [PMID: 29339798]
[http://dx.doi.org/10.1038/nature08849] [PMID: 20305637]
[http://dx.doi.org/10.1101/cshperspect.a016766] [PMID: 24003212]
[http://dx.doi.org/10.1074/jbc.M301642200] [PMID: 12639953]
[http://dx.doi.org/10.1016/j.cub.2009.09.059] [PMID: 19896381]
[http://dx.doi.org/10.1021/bi9805238] [PMID: 9799499]
[http://dx.doi.org/10.1073/pnas.1410041111] [PMID: 24938788]
[http://dx.doi.org/10.4161/cib.26631] [PMID: 24567776]
[http://dx.doi.org/10.1038/s41598-019-52513-x] [PMID: 31695092]
[http://dx.doi.org/10.3389/fbioe.2020.00633] [PMID: 32671037]
[http://dx.doi.org/10.1002/1521-4141(2001010)31:10<2892:AID-IMMU2892>3.0.CO;2-I] [PMID: 11592064]
[http://dx.doi.org/10.1083/jcb.41.1.59] [PMID: 5775794]
[http://dx.doi.org/10.1007/BF00255932] [PMID: 6219486]
[http://dx.doi.org/10.1016/j.tcb.2015.01.004] [PMID: 25683921]
[http://dx.doi.org/10.1042/bj2740381] [PMID: 1848755]
[http://dx.doi.org/10.1016/j.ymeth.2015.04.008] [PMID: 25890246]
[http://dx.doi.org/10.18632/oncotarget.3598] [PMID: 25857301]
[http://dx.doi.org/10.18632/oncotarget.3801] [PMID: 25944692]
[http://dx.doi.org/10.3402/jev.v5.32570] [PMID: 27863537]
[http://dx.doi.org/10.1002/stem.2922] [PMID: 30353966]
[http://dx.doi.org/10.1080/20013078.2018.1535750] [PMID: 30637094]
[http://dx.doi.org/10.1080/20013078.2018.1505403] [PMID: 30108686]
[http://dx.doi.org/10.1080/20013078.2019.1689784] [PMID: 31839905]
[http://dx.doi.org/10.1101/gad.192351.112] [PMID: 22713869]
[http://dx.doi.org/10.1038/nri3622] [PMID: 24566916]
[http://dx.doi.org/10.7717/peerj-achem.4]
[http://dx.doi.org/10.1128/AAC.01823-17] [PMID: 29066454]
[http://dx.doi.org/10.1007/s00281-010-0228-6] [PMID: 20941495]
[http://dx.doi.org/10.2174/1568009615666150225121508] [PMID: 25714701]
[http://dx.doi.org/10.1111/acel.12734] [PMID: 29392820]
[http://dx.doi.org/10.2174/1566524019666190314120532] [PMID: 30868953]
[http://dx.doi.org/10.1002/cpim.17] [PMID: 27801511]
[http://dx.doi.org/10.1074/jbc.M112.404467] [PMID: 23129776]
[http://dx.doi.org/10.2337/db09-0216] [PMID: 19675137]
[http://dx.doi.org/10.1080/20013078.2017.1348885] [PMID: 28804598]
[http://dx.doi.org/10.1016/j.metabol.2019.02.006] [PMID: 30831143]
[http://dx.doi.org/10.1155/2018/8545347] [PMID: 29662902]
[http://dx.doi.org/10.3402/jev.v2i0.20360]
[http://dx.doi.org/10.3402/jev.v5.32945] [PMID: 27802845]
[http://dx.doi.org/10.3402/jev.v3.23111] [PMID: 24678386]
[http://dx.doi.org/10.1186/s12931-019-1210-z] [PMID: 31666080]
[http://dx.doi.org/10.1016/0042-6822(70)90218-7] [PMID: 4908735]
[http://dx.doi.org/10.3402/jev.v3.23430] [PMID: 25279113]
[http://dx.doi.org/10.1038/srep33641] [PMID: 27640641]
[http://dx.doi.org/10.1038/s12276-019-0219-1] [PMID: 30872565]
[http://dx.doi.org/10.1016/j.jim.2014.04.003] [PMID: 24735771]
[http://dx.doi.org/10.1038/srep23978] [PMID: 27068479]
[http://dx.doi.org/10.1038/s41598-018-24163-y] [PMID: 29636530]
[http://dx.doi.org/10.1002/prca.200800093] [PMID: 21137018]
[http://dx.doi.org/10.1002/biot.201700716] [PMID: 29878510]
[http://dx.doi.org/10.3171/2014.11.JNS14770] [PMID: 25594326]
[http://dx.doi.org/10.1016/j.stemcr.2016.01.001] [PMID: 26923821]
[http://dx.doi.org/10.7150/thno.20746] [PMID: 29463990]
[http://dx.doi.org/10.14814/phy2.14172] [PMID: 31325249]
[http://dx.doi.org/10.1038/s41598-019-41100-9] [PMID: 30872726]
[http://dx.doi.org/10.1111/jcmm.14190] [PMID: 30772948]
[http://dx.doi.org/10.3390/cells8080855] [PMID: 31398924]
[http://dx.doi.org/10.1002/jcp.28891] [PMID: 31144307]
[http://dx.doi.org/10.1016/j.jconrel.2014.07.042] [PMID: 25084218]
[http://dx.doi.org/10.2147/IJN.S210731] [PMID: 31413568]
[http://dx.doi.org/10.1038/srep32993] [PMID: 27615560]
[http://dx.doi.org/10.1111/cpr.12669] [PMID: 31380594]
[http://dx.doi.org/10.1186/s13287-018-0939-5] [PMID: 29996938]
[http://dx.doi.org/10.1016/j.biomaterials.2017.11.028] [PMID: 29182933]
[http://dx.doi.org/10.1089/scd.2013.0479] [PMID: 24367916]
[http://dx.doi.org/10.1038/sj.bdj.2018.348] [PMID: 29725075]
[http://dx.doi.org/10.1073/pnas.0937635100] [PMID: 12716973]
[http://dx.doi.org/10.1155/2018/8973613] [PMID: 29760738]
[http://dx.doi.org/10.1007/s10517-005-0232-3] [PMID: 16142297]
[PMID: 20388961]
[http://dx.doi.org/10.1007/s12015-016-9715-z]
[http://dx.doi.org/10.1038/nrm2183] [PMID: 17522591]
[http://dx.doi.org/10.2174/22115528113020020001] [PMID: 25374792]
[http://dx.doi.org/10.1089/scd.2012.0095] [PMID: 22839741]
[http://dx.doi.org/10.1002/sctm.19-0432] [PMID: 32761804]
[http://dx.doi.org/10.1038/nature04479] [PMID: 16355211]
[http://dx.doi.org/10.1038/nrm1911] [PMID: 16633338]
[http://dx.doi.org/10.1016/j.jash.2013.01.004] [PMID: 23428409]
[http://dx.doi.org/10.1186/scrt465] [PMID: 24915963]
[http://dx.doi.org/10.1155/2017/7407168] [PMID: 28573141]
[http://dx.doi.org/10.1186/1478-811X-12-26] [PMID: 24725987]
[http://dx.doi.org/10.1093/cvr/cvn156] [PMID: 18550634]
[http://dx.doi.org/10.1093/nar/gkp857] [PMID: 19850715]
[http://dx.doi.org/10.1186/s13287-015-0116-z] [PMID: 26129847]
[http://dx.doi.org/10.1089/scd.2011.0500] [PMID: 22142236]
[http://dx.doi.org/10.1159/000438594] [PMID: 26646808]
[http://dx.doi.org/10.1371/journal.pone.0072383] [PMID: 23991105]
[http://dx.doi.org/10.1002/jcp.28070] [PMID: 30720220]
[http://dx.doi.org/10.1161/JAHA.115.002856] [PMID: 26811168]
[http://dx.doi.org/10.1155/2018/3290372] [PMID: 30271437]
[http://dx.doi.org/10.3892/mmr.2018.8620] [PMID: 29484401]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.093906] [PMID: 23136161]
[http://dx.doi.org/10.1038/ncb2574] [PMID: 22983114]
[http://dx.doi.org/10.15252/embj.201488598] [PMID: 24825347]
[http://dx.doi.org/10.5966/sctm.2014-0267] [PMID: 25824139]
[http://dx.doi.org/10.1371/journal.pone.0084256] [PMID: 24391924]
[http://dx.doi.org/10.2147/vhrm.2006.2.3.213] [PMID: 17326328]
[http://dx.doi.org/10.1016/S0002-9440(10)64887-0] [PMID: 11839588]
[http://dx.doi.org/10.1593/neo.07133] [PMID: 17460779]
[http://dx.doi.org/10.1186/s12929-018-0491-8] [PMID: 30572957]
[http://dx.doi.org/10.1016/j.addr.2014.11.010] [PMID: 25446133]
[http://dx.doi.org/10.1007/BF01246356] [PMID: 8478639]
[http://dx.doi.org/10.1002/(SICI)1098-2752(1998)18:7<397: AID-MICR2>3.0.CO;2-F] [PMID: 9880154]
[http://dx.doi.org/10.1089/ten.tea.2018.0176] [PMID: 30311853]
[http://dx.doi.org/10.1007/s12015-016-9713-1]
[http://dx.doi.org/10.1177/1545968318798955] [PMID: 30223738]
[http://dx.doi.org/10.1038/nn.3935] [PMID: 25643297]
[http://dx.doi.org/10.18632/oncotarget.3211] [PMID: 25669974]
[http://dx.doi.org/10.1002/glia.22606] [PMID: 24339157]
[http://dx.doi.org/10.1002/stem.1409] [PMID: 23630198]
[PMID: 31966893]
[http://dx.doi.org/10.1016/j.neuroscience.2016.01.061] [PMID: 26851773]
[http://dx.doi.org/10.1002/glia.22558] [PMID: 24038411]
[http://dx.doi.org/10.1002/glia.21196] [PMID: 21656857]
[http://dx.doi.org/10.1016/j.jcyt.2015.01.005] [PMID: 25743633]
[http://dx.doi.org/10.1007/s12035-018-1172-z] [PMID: 29931510]
[http://dx.doi.org/10.1089/scd.2011.0244] [PMID: 22008016]
[http://dx.doi.org/10.3390/cells9010163] [PMID: 31936601]
[http://dx.doi.org/10.3390/cells8121497] [PMID: 31771176]
[http://dx.doi.org/10.1177/0963689719870999] [PMID: 31423807]
[http://dx.doi.org/10.1021/acsnano.9b01004] [PMID: 31117376]
[http://dx.doi.org/10.1016/S0140-6736(08)61620-7] [PMID: 18970977]
[http://dx.doi.org/10.1093/brain/awp300] [PMID: 19952055]
[http://dx.doi.org/10.1038/srep01197] [PMID: 23378928]
[http://dx.doi.org/10.3233/JAD-2010-1221] [PMID: 20061647]
[http://dx.doi.org/10.1016/S0304-3940(00)01675-X] [PMID: 11121879]
[http://dx.doi.org/10.1016/j.jcyt.2014.07.013] [PMID: 25981557]
[http://dx.doi.org/10.18632/oncotarget.12902] [PMID: 27793019]
[http://dx.doi.org/10.1002/hep.30305] [PMID: 30296341]
[http://dx.doi.org/10.1016/j.jhep.2015.07.030] [PMID: 26254847]
[http://dx.doi.org/10.1089/scd.2012.0395] [PMID: 23002959]
[http://dx.doi.org/10.1002/sctm.16-0226] [PMID: 28213967]
[http://dx.doi.org/10.1080/20013078.2017.1310414]
[http://dx.doi.org/10.1016/j.diabres.2018.02.023] [PMID: 29496507]
[http://dx.doi.org/10.2215/CJN.05021107] [PMID: 18256371]
[http://dx.doi.org/10.1681/ASN.2008070798] [PMID: 19389847]
[PMID: 31217862]
[http://dx.doi.org/10.1371/journal.pone.0044092] [PMID: 22970165]
[http://dx.doi.org/10.1186/s13287-019-1227-8] [PMID: 30995947]
[http://dx.doi.org/10.1089/scd.2012.0266] [PMID: 23082760]
[http://dx.doi.org/10.1186/scrt514] [PMID: 25384729]
[http://dx.doi.org/10.1186/s13287-017-0478-5] [PMID: 28173878]
[http://dx.doi.org/10.1371/journal.pone.0087853] [PMID: 24504266]
[http://dx.doi.org/10.1186/scrt194] [PMID: 23618405]
[http://dx.doi.org/10.1186/scrt428] [PMID: 24646750]
[http://dx.doi.org/10.1155/2016/2093940] [PMID: 27799943]
[http://dx.doi.org/10.1016/j.kint.2016.12.023] [PMID: 28242034]
[http://dx.doi.org/10.1186/s13287-016-0287-2] [PMID: 26852014]
[http://dx.doi.org/10.1038/nature07039] [PMID: 18480812]
[http://dx.doi.org/10.1001/archderm.139.4.510] [PMID: 12707099]
[http://dx.doi.org/10.1038/nrc1802] [PMID: 16491069]
[http://dx.doi.org/10.1016/j.yexcr.2018.06.035] [PMID: 29964051]
[http://dx.doi.org/10.1007/s10456-017-9554-9] [PMID: 28391377]
[http://dx.doi.org/10.1186/s13287-019-1152-x] [PMID: 30704535]
[http://dx.doi.org/10.1038/srep07144] [PMID: 25413454]
[http://dx.doi.org/10.1002/sctm.16-0428] [PMID: 28198592]
[http://dx.doi.org/10.1167/iovs.18-25310] [PMID: 30452601]
[http://dx.doi.org/10.1038/srep34562] [PMID: 27686625]
[http://dx.doi.org/10.7150/thno.28021] [PMID: 30613290]
[http://dx.doi.org/10.1016/j.semcdb.2016.11.008] [PMID: 27871993]
[http://dx.doi.org/10.1186/s13005-016-0101-5] [PMID: 26772731]
[PMID: 25834689]
[http://dx.doi.org/10.1111/ijd.12650] [PMID: 25777970]
[http://dx.doi.org/10.1126/scisignal.2005231] [PMID: 24985346]