Molecular Mechanisms Responsible for Therapeutic Potential of Mesenchymal Stem Cell-Derived Secretome

Carl Randall Harrell, Crissy Fellabaum, Nemanja Jovicic, Valentin Djonov, Nebojsa Arsenijevic, Vladislav Volarevic, Carl Randall Harrell, Crissy Fellabaum, Nemanja Jovicic, Valentin Djonov, Nebojsa Arsenijevic, Vladislav Volarevic

Abstract

Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including unwanted differentiation of engrafted MSCs. In contrast to MSCs which had to be expanded in culture to reach optimal cell number for transplantation, MSC-sourced secretome is immediately available for treatment of acute conditions, including fulminant hepatitis, cerebral ischemia and myocardial infarction. Additionally, MSC-derived secretome could be massively produced from commercially available cell lines avoiding invasive cell collection procedure. In this review article we emphasized molecular and cellular mechanisms that were responsible for beneficial effects of MSC-derived secretomes in the treatment of degenerative and inflammatory diseases of hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular and nervous system. Results obtained in a large number of studies suggested that administration of MSC-derived secretomes represents a new, cell-free therapeutic approach for attenuation of inflammatory and degenerative diseases. Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration.

Keywords: degenerative diseases; inflammatory diseases; mesenchymal stem cells; secretome; therapy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular mechanisms responsible for beneficial effects of MSC-derived secretome in asthma. Administration of MSC-sourced secretome significantly reduced influx of circulating eosinophils, neutrophils, monocytes and lymphocytes in asthmatic lungs resulting in alleviation of on-going inflammation. MSC-CM or MSC-Exos reduced TGF-β production, decreased collagen deposition and attenuated fibrosis in the lungs. Additionally, MSC-derived secretome attenuated antigen-presenting function of DCs and suppressed Th2 and Th17 cell-driven inflammatory response in asthmatic lungs, but increased total number of lung-infiltrated IL-10-producing Tregs which created immunosuppressive microenvironment that allowed better functional recovery of asthmatic animals.
Figure 2
Figure 2
Herapeutic effects of MSC-derived secretome in cartilage regeneration. Chondrocytes cultured in the presence of MSC-derived secretome significantly reduce production of inflammatory cytokines which play detrimental role in cartilage degeneration during OA development (TNF-α, IL-1β, IL-6, nitric oxide (NO)) and increase production of immunosuppressive IL-10 which protects cartilage from inflammation-related injury. Accelerated neotissue filling and increased synthesis of type II collagen were noticed in osteoarthritic animals that received MSC-sourced secretome. MSC-derived extracellular vesicles (EVs) promoted endogenous cartilage repair and regeneration by delivering miR-320c and miR-92a-3p which restore homeostasis in bioenergetics and cell metabolism in proliferating chondrocytes.
Figure 3
Figure 3
Therapeutic effects of MSC-derived secretome in attenuation of experimental colitis. Administration of MSC-sourced extracellular vesicles (EVs), including MSC-derived exosomes (Exos), efficiently alleviated dextran sodium sulphate (DSS)-induced colitis. Intravenous injection of MSC-EVs significantly decreased activity of myeloperoxidase (MPO), malondialdehyde (MDA) and notably increased expression of superoxide dismutase (SOD) and glutathione (GSH) in inflamed colons, indicating that modulation of anti-oxidant/oxidant balance in inflamed gut had important role for MSC-EVs-based therapeutic effects. Down-regulation of ubiquitin and ubiquitin-associated molecules (K48, K63 and FK2) in inflamed gut were also responsible for MSC-Exo-based attenuation of colitis. Additionally, MSC-derived secretome attenuated production of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-7) in colon macrophages resulting in alleviation of on-going inflammation.
Figure 4
Figure 4
Therapeutic potential of MSC-sourced secretome in myocardial regeneration. MSC-derived secretome promote myocardial regeneration by preventing apoptosis of cardiomyocytes, by inducing neo-angiogenesis in ischemic regions and by promoting survival, angiogenic potency and capacity for self-renewal of cardiac stem cells (CSCs). MSC-derived extracellular vesicles (EVs) increased survival of cardiomyocytes in ischemic lesions by preventing apoptosis and by inducing autophagy via modulation of AMPK/mTOR, Akt/mTOR and Wnt/β-catenin pathways. Administration of MSC-derived exosomes (Exos) resulted in up-regulation of anti-apoptotic Bcl-2, down-regulation of pro-apoptotic Bax and suppressed activity of caspase-3 in cardiomyocytes. MSC-Exos-mediated delivery of miR-210 and miR-125b-5p increased survival of cardiomyocytes by preventing p53 and Bak1-driven apoptosis. MSC-Exo-mediated delivery of stromal cell-derived factor-1 (SDF-1) and miR-132 resulted in enhanced tube formation and increased angiogenic capacity of endothelial cells (ECs). MSC-Exos-mediated modulation of CSCs function has been attributed to the delivery of miR-15, miR-21, miR-22, miR-126, miR-146a, miR-210 which prevented apoptosis and promoted survival of CSCs.
Figure 5
Figure 5
Molecular mechanisms responsible for beneficial effects of MSC-derived secretome in retinal regeneration. MSC-derived exosomes (Exos) promote regeneration of injured retina by supplying retinal ganglion cells (RGCs) with miR-17-92, miR-21, miR146a and neurotrophins (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and platelet-derived growth factor (PDGF)). MSC-sourced secretome suppress detrimental immune response in the eye through the inhibition of antigen-presenting cells (macrophages and dendritic cells (DCs)) which results in attenuated activation of Th1 and Th17 cells and alleviation of retinal injury and inflammation.
Figure 6
Figure 6
Molecular mechanisms responsible for beneficial effects of MSC-derived secretomes in the therapy of ischemic brain damage and spinal cord injury. Administration of MSC-sourced extracellular vesicles (EVs), including MSC-derived exosomes (Exos), promoted neural regeneration in animal models of ischemic brain damage and spinal cord injury (SCI). MSC-Exos-based therapy improved neurogenesis, promoted axonal growth, increased presence of neuroblasts and endothelial cells (ECs) in ischemic regions of the brain. MSCs-Exo regulated neurogenesis by supplying neurons with miR-133b which promoted neurite outgrowth by targeting Ras homolog gene family member A (RhoA). Similarly, systemic injection of miR-133b-bearing MSC-Exos promoted recovery from SCI by promoting regeneration of axons through the activation of survival Erk1/2 and Stat-3 signaling pathways in regenerating neurons. After intravenous administration, MSC-Exos accumulated at the site of SCI and promoted generation of immunosuppressive M2 macrophages which, in IL-10-dependent manner, suppressed activation of neurotoxic A1 astrocytes through the inhibition of NF-kB. In similar manner, via down-regulation of NF-κB p65 signaling, MSC-EVs reduced migratory capacities of pericytes and maintained structural integrity of blood-spinal cord barrier (BSCB).
Figure 7
Figure 7
Molecular mechanisms responsible for beneficial effects of MSC-derived secretome in tissue repair and regeneration. Results obtained in experimental studies suggest that MSC-derived secretome represents a promising therapeutic tool for the treatment of degenerative and inflammatory diseases. Beneficial effects of MSC-sourced secretomes rely on their capacity to deliver neurotrophins (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), hepatocyte growth factor (HGF), miR-17-92, miR-21, miR-124, miR-133b, miR146a which enable regeneration of injured liver, brain, spinal cord and eye. MSC-derived secretomes contain immunomodulatory factors which inhibit proliferation and activation of inflammatory immune cells and promote expansion of immunosuppressive cells resulting in alleviation of inflammation-related tissue injury. MSC-sourced secretomes are enriched with angiomodulatory factors (stromal cell derived factor-1 (SDF-1), miR-132, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF)) that promote angiogenesis and neo-vascularization in ischemic regions of brain and heart enhancing survival of injured neurons and cardiomyocytes.

References

    1. Kuriyan A.E., Albini T.A., Townsend J.H., Rodriguez M., Pandya H.K., Leonard R.E., 2nd, Parrott M.B., Rosenfeld P.J., Flynn H.W., Jr., Goldberg J.L. Vision Loss after Intravitreal Injection of Autologous “Stem Cells” for AMD. N. Engl. J. Med. 2017;376:1047–1053. doi: 10.1056/NEJMoa1609583.
    1. Glassberg M.K., Minkiewicz J., Toonkel R.L., Simonet E.S., Rubio G.A., DiFede D., Shafazand S., Khan A., Pujol M.V., LaRussa V.F., et al. Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial. Chest. 2017;151:971–981. doi: 10.1016/j.chest.2016.10.061.
    1. Lindsay J.O., Allez M., Clark M., Labopin M., Ricart E., Rogler G., Rovira M., Satsangi J., Farge D., Hawkey C.J., ASTIC Trial Group. European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. European Crohn’s and Colitis Organisation Autologous stem-cell transplantation in treatment-refractory Crohn’s disease: An analysis of pooled data from the ASTIC trial. Lancet Gastroenterol. Hepatol. 2017;2:399–406. doi: 10.1016/S2468-1253(17)30056-0.
    1. Ryan J.M., Barry F.P., Murphy J.M., Mahon B.P. Mesenchymal stem cells avoid allogeneic rejection. J. Inflamm. (Lond.) 2005;2 doi: 10.1186/1476-9255-2-8.
    1. Gazdic M., Volarevic V., Arsenijevic N., Stojkovic M. Mesenchymal stem cells: A friend or foe in immune-mediated diseases. Stem Cell Rev. 2015;11:280–287. doi: 10.1007/s12015-014-9583-3.
    1. Meier R.P., Müller Y.D., Morel P., Gonelle-Gispert C., Bühler L.H. Transplantation of mesenchymal stem cells for the treatment of liver diseases, is there enough evidence? Stem Cell Res. 2013;11:1348–1364. doi: 10.1016/j.scr.2013.08.011.
    1. Soukup T., Mokrý J., Karbanová J., Pytlík R., Suchomel P., Kucerová L. Mesenchymal stem cells isolated from the human bone marrow: Cultivation, phenotypic analysis and changes in proliferation kinetics. Acta Medica (Hradec Kralove) 2006;49:27–33. doi: 10.14712/18059694.2017.106.
    1. Gou S., Wang C., Liu T., Wu H., Xiong J., Zhou F., Zhao G. Spontaneous differentiation of murine bone marrow-derived mesenchymal stem cells into adipocytes without malignant transformation after long-term culture. Cells Tissues Organs. 2010;191:185–192. doi: 10.1159/000240246.
    1. Hao W., Shi S., Zhou S., Wang X., Nie S. Aspirin inhibits growth and enhances cardiomyocyte differentiation of bone marrow mesenchymal stem cells. Eur. J. Pharmacol. 2018;827:198–207. doi: 10.1016/j.ejphar.2018.03.016.
    1. Mikael P.E., Willard C., Koyee A., Barlao C.G., Liu X., Han X., Ouyang Y., Xia K., Linhardt R.J., Dordick J.S. Remodeling of Glycosaminoglycans During Differentiation of Adult Human Bone Mesenchymal Stromal Cells Toward Hepatocytes. Stem Cells Dev. 2019;28:278–289. doi: 10.1089/scd.2018.0197.
    1. Urrutia D.N., Caviedes P., Mardones R., Minguell J.J., Vega-Letter A.M., Jofre C.M. Comparative study of the neural differentiation capacity of mesenchymal stromal cells from different tissue sources: An approach for their use in neural regeneration therapies. PLoS ONE. 2019;14:e0213032. doi: 10.1371/journal.pone.0213032.
    1. Jiao X., Lv Q., Cao S.N. MicroRNA-26b-5p promotes development of neonatal respiratory distress syndrome by inhibiting differentiation of mesenchymal stem cells to type II of alveolar epithelial cells via regulating Wnt5a. Eu.r Rev. Med. Pharmacol. Sci. 2019;23:1681–1687. doi: 10.26355/eurrev_201902_17130.
    1. Lou. G., Chen Z., Zheng M., Liu Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Exp. Mol. Med. 2017;49:e346. doi: 10.1038/emm.2017.63.
    1. Gazdic M., Arsenijevic A., Markovic B.S., Volarevic A., Dimova I., Djonov V., Arsenijevic N., Stojkovic M., Volarevic V. Mesenchymal Stem Cell-Dependent Modulation of Liver Diseases. Int. J. Biol. Sci. 2017;13:1109–1117. doi: 10.7150/ijbs.20240.
    1. Van Poll D., Parekkadan B., Cho C.H., Berthiaume F., Nahmias Y., Tilles A.W., Yarmush M.L. Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008;47:1634–1643. doi: 10.1002/hep.22236.
    1. Xagorari A., Siotou E., Yiangou M., Tsolaki E., Bougiouklis D., Sakkas L., Fassas A., Anagnostopoulos A. Protective effect of mesenchymal stem cell-conditioned medium on hepatic cell apoptosis after acute liver injury. Int. J. Clin. Exp. Pathol. 2013;6:831–840.
    1. Parekkadan B., van Poll D., Megeed Z., Kobayashi N., Tilles A.W., Berthiaume F., Yarmush M.L. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem. Biophys. Res. Commun. 2007;363:247–252. doi: 10.1016/j.bbrc.2007.05.150.
    1. Milosavljevic N., Gazdic M., Simovic Markovic B., Arsenijevic A., Nurkovic J., Dolicanin Z., Jovicic N., Jeftic I., Djonov V., Arsenijevic N., et al. Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells—An experimental study. Transpl. Int. 2018;31:102–115. doi: 10.1111/tri.13023.
    1. Zhu Y.G., Feng X.M., Abbott J., Fang X.H., Hao Q., Monsel A., Qu J.M., Matthay M.A., Lee J.W. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells. 2014;32:116–125. doi: 10.1002/stem.1504.
    1. Takeoka M., Ward W.F., Pollack H., Kamp D.W., Panos R.J. KGF facilitates repair of radiation-induced DNA damage in alveolar epithelial cells. Am. J. Physiol. 1997;272:L1174–L1180. doi: 10.1152/ajplung.1997.272.6.L1174.
    1. Li J.W., Wu X. Mesenchymal stem cells ameliorate LPS-induced acute lung injury through KGF promoting alveolar fluid clearance of alveolar type II cells. Eur. Rev. Med. Pharmacol. Sci. 2015;19:2368–2378.
    1. Monsel A., Zhu Y.G., Gennai S., Hao Q., Hu S., Rouby J.J., Rosenzwajg M., Matthay M.A., Lee J.W. Therapeutic Effects of Human Mesenchymal Stem Cell-derived Microvesicles in Severe Pneumonia in Mice. Am. J. Respir. Crit. Care Med. 2015;192:324–336. doi: 10.1164/rccm.201410-1765OC.
    1. Broekman W., Khedoe P.P.S.J., Schepers K., Roelofs H., Stolk J., Hiemstra P.S. Mesenchymal stromal cells: A novel therapy for the treatment of chronic obstructive pulmonary disease? Thorax. 2018;73:565–574. doi: 10.1136/thoraxjnl-2017-210672.
    1. Kim S.Y., Lee J.H., Kim H.J., Park M.K., Huh J.W., Ro J.Y., Oh Y.M., Lee S.D., Lee Y.S. Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. Am. J. Physiol. Lung. Cell. Mol. Physiol. 2012;302:L891–L908. doi: 10.1152/ajplung.00288.2011.
    1. Kim Y.S., Kim J.Y., Cho R., Shin D.M., Lee S.W., Oh Y.M. Adipose stem cell-derived nanovesicles inhibit emphysema primarily via an FGF2-dependent pathway. Exp. Mol. Med. 2017;49:e284. doi: 10.1038/emm.2016.127.
    1. Zhang S., Chu W.C., Lai R.C., Lim S.K., Hui J.H., Toh W.S. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage. 2016;24:2135–2140. doi: 10.1016/j.joca.2016.06.022.
    1. Toh W.S., Lai R.C., Hui J.H.P., Lim S.K. MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin. Cell. Dev. Biol. 2017;67:56–64. doi: 10.1016/j.semcdb.2016.11.008.
    1. Mao F., Wu Y., Tang X., Kang J., Zhang B., Yan Y., Qia H., Zhang X., Xu W. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Inflammatory Bowel Disease in Mice. Biomed. Res. Int. 2017;2017 doi: 10.1155/2017/5356760.
    1. Yang J., Liu X.X., Fan H., Tang Q., Shou Z.X., Zuo D.M., Zou Z., Xu M., Chen Q.Y., Peng Y., et al. Extracellular Vesicles Derived from Bone Marrow Mesenchymal Stem Cells Protect against Experimental Colitis via Attenuating Colon Inflammation, Oxidative Stress and Apoptosis. PLoS ONE. 2015;10:e0140551. doi: 10.1371/journal.pone.0140551.
    1. Hetzenecker A.M., Seidl M.C., Kosovac K., Herfarth H., Kellermeier S., Obermeier F., Falk W., Schoelmerich J., Hausmann M., Rogler G. Downregulation of the ubiquitin-proteasome system in normal colonic macrophages and reinduction in inflammatory bowel disease. Digestion. 2012;86:34–47. doi: 10.1159/000336353.
    1. Lai R.C., Arslan F., Lee M.M., Sze N.S., Choo A., Chen T.S., Salto-Tellez M., Timmers L., Lee C.N., El Oakley R.M., et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4:214–222. doi: 10.1016/j.scr.2009.12.003.
    1. Arslan F., Lai R.C., Smeets M.B., Akeroyd L., Choo A., Aguor E.N., Timmers L., van Rijen H.V., Dovendans P.A., Pasterkamp G., et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 2013;10:301–312. doi: 10.1016/j.scr.2013.01.002.
    1. Yu B., Kim H.W., Gong M., Wang J., Millard R.W., Wang Y., Ashraf M., Xu M. Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int. J. Cardiol. 2015;182:349–360. doi: 10.1016/j.ijcard.2014.12.043.
    1. Yu B., Shao H., Su C., Jiang Y., Chen X., Bai L., Zhang Y., Li Q., Zhang X., Li X. Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci. Rep. 2016;6 doi: 10.1038/srep34562.
    1. Bai L., Shao H., Wang H., Zhang Z., Su C., Dong L., Yu B., Chen X., Li X., Zhang X. Effects of Mesenchymal Stem Cell-Derived Exosomes on Experimental Autoimmune Uveitis. Sci. Rep. 2017;7 doi: 10.1038/s41598-017-04559-y.
    1. Xin H., Li Y., Buller B., Katakowski M., Zhang Y., Wang X., Shang X., Zhang Z.G., Chopp M. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells. 2012;30:1556–1564. doi: 10.1002/stem.1129.
    1. Vizoso F.J., Eiro N., Cid S., Schneider J., Perez-Fernandez R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int. J. Mol. Sci. 2017;18:1852. doi: 10.3390/ijms18091852.
    1. Ferreira J.R., Teixeira G.Q., Santos S.G., Barbosa M.A., Almeida-Porada G., Gonçalves R.M. Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning. Front. Immunol. 2018;9 doi: 10.3389/fimmu.2018.02837.
    1. Cunningham C.J., Redondo-Castro E., Allan S.M. The therapeutic potential of the mesenchymal stem cell secretome in ischaemic stroke. J. Cereb. Blood Flow Metab. 2018;38:1276–1292. doi: 10.1177/0271678X18776802.
    1. Maguire G. Stem cell therapy without the cells. Commun. Integr. Biol. 2013;6:e26631. doi: 10.4161/cib.26631.
    1. Vishnubhatla I., Corteling R., Stevanato L., Hicks C., Sinden J. The Development of Stem Cell-Derived Exosomes as a Cell-Free Regenerative Medicine. J. Circ. Biomark. 2014;3 doi: 10.5772/58597.
    1. Bright J.J., Kerr L.D., Sriram S. TGF-beta inhibits IL-2-induced tyrosine phosphorylation and activation of Jak-1 and Stat 5 in T lymphocytes. J. Immunol. 1997;159:175–183.
    1. Harrell C.R., Simovic Markovic B., Fellabaum C., Arsenijevic A., Djonov V., Arsenijevic N., Volarevic V. Therapeutic Potential of Mesenchymal Stem Cell-Derived Exosomes in the Treatment of Eye Diseases. Adv. Exp. Med. Biol. 2018;1089:47–57. doi: 10.1007/5584_2018_219.
    1. Fan Y., Herr F., Vernochet A., Mennesson B., Oberlin E., Durrbach A. Human Fetal Liver Mesenchymal Stem Cell-Derived Exosomes Impair Natural Killer Cell Function. Stem Cells Dev. 2019;28:44–55. doi: 10.1089/scd.2018.0015.
    1. Di Nicola M., Carlo-Stella C., Magni M., Milanesi M., Longoni P.D., Matteucci P., Grisanti S., Gianni A.M. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–3843. doi: 10.1182/blood.V99.10.3838.
    1. Chen W., Huang Y., Han J., Yu L., Li Y., Lu Z., Li H., Liu Z., Shi C., Duan F., et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol. Res. 2016;64:831–840. doi: 10.1007/s12026-016-8798-6.
    1. Zhang Q., Fu L., Liang Y., Guo Z., Wang L., Ma C., Wang H. Exosomes originating from MSCs stimulated with TGF-β and IFN-γ promote Treg differentiation. J. Cell. Physiol. 2018;233:6832–6840. doi: 10.1002/jcp.26436.
    1. Acovic A., Gazdic M., Jovicic N., Harrell C.R., Fellabaum C., Arsenijevic N., Volarevic V. Role of indoleamine 2,3-dioxygenase in pathology of the gastrointestinal tract. Therap. Adv. Gastroenterol. 2018;11 doi: 10.1177/1756284818815334.
    1. Showalter M.R., Wancewicz B., Fiehn O., Archard J.A., Clayton S., Wagner J., Deng P., Halmai J., Fink K.D., Bauer G., et al. Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation. Biochem. Biophys. Res. Commun. 2019;512:729–735. doi: 10.1016/j.bbrc.2019.03.119.
    1. Li Z., Liu F., He X., Yang X., Shan F., Feng J. 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. 2019;67:268–280. doi: 10.1016/j.intimp.2018.12.001.
    1. Su T., Xiao Y., Xiao Y., Guo Q., Li C., Huang Y., Deng Q., Wen J., Zhou F., Luo X.H. Bone Marrow Mesenchymal Stem Cells-Derived Exosomal MiR-29b-3p Regulates Aging-Associated Insulin Resistance. ACS Nano. 2019;13:2450–2462. doi: 10.1021/acsnano.8b09375.
    1. Nojehdehi S., Soudi S., Hesampour A., Rasouli S., Soleimani M., Hashemi S.M. Immunomodulatory effects of mesenchymal stem cell-derived exosomes on experimental type-1 autoimmune diabetes. J. Cell. Biochem. 2018;119:9433–9443. doi: 10.1002/jcb.27260.
    1. Hosseini S.F., Alibolandi M., Rafatpanah H., Abnous K., Mahmoudi M., Kalantari M., Taghdisi S.M., Ramezani M. 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. 2019;299:149–164. doi: 10.1016/j.jconrel.2019.02.032.
    1. Seo Y., Kim H.S., Hong I.S. Stem Cell-Derived Extracellular Vesicles as Immunomodulatory Therapeutics. Stem Cells Int. 2019;2019:5126156. doi: 10.1155/2019/5126156.
    1. Li Y., Wang F., Guo R., Zhang Y., Chen D., Li X., Tian W., Xie X., Jiang Z. Exosomal sphingosine 1-phosphate secreted by mesenchymal stem cells regulated Treg/Th17 balance in aplastic anemia. IUBMB Life. 2019 doi: 10.1002/iub.2035.
    1. Kou X., Xu X., Chen C., Sanmillan M.L., Cai T., Zhou Y., Giraudo C., Le A., Shi S. The Fas/Fap-1/Cav-1 complex regulates IL-1RA secretion in mesenchymal stem cells to accelerate wound healing. Sci. Transl. Med. 2018;10 doi: 10.1126/scitranslmed.aai8524.
    1. Volarevic V., Al-Qahtani A., Arsenijevic N., Pajovic S., Lukic M.L. Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity. 2010;43:255–263. doi: 10.3109/08916930903305641.
    1. Ortiz L.A., Dutreil M., Fattman C., Pandey A.C., Torres G., Go K., Phinney D.G. Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc. Natl. Acad. Sci. USA. 2007;104:11002–11007. doi: 10.1073/pnas.0704421104.
    1. Harting M.T., Srivastava A.K., Zhaorigetu S., Bair H., Prabhakara K.S., Toledano Furman N.E., Vykoukal J.V., Ruppert K.A., Cox C.S., Jr., Olson S.D. Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation. Stem Cells. 2018;36:79–90. doi: 10.1002/stem.2730.
    1. Volarevic V., Gazdic M., Simovic Markovic B., Jovicic N., Djonov V., Arsenijevic N. Mesenchymal stem cell-derived factors: Immuno-modulatory effects and therapeutic potential. Biofactors. 2017;43:633–644. doi: 10.1002/biof.1374.
    1. Kalinski P. Regulation of immune responses by prostaglandin E2. J. Immunol. 2012;188:21–28. doi: 10.4049/jimmunol.1101029.
    1. Villatoro A.J., Alcoholado C., Martín-Astorga M.C., Fernández V., Cifuentes M., Becerra J. Comparative analysis and characterization of soluble factors and exosomes from cultured adipose tissue and bone marrow mesenchymal stem cells in canine species. Vet. Immunol. Immunopathol. 2019;208:6–15. doi: 10.1016/j.vetimm.2018.12.003.
    1. Bermudez M.A., Sendon-Lago J., Eiro N., Treviño M., Gonzalez F., Yebra-Pimentel E., Giraldez M.J., Macia M., Lamelas M.L., Saa J., et al. Corneal epithelial wound healing and bactericidal effect of conditioned medium from human uterine cervical stem cells. Invest. Ophthalmol. Vis. Sci. 2015;56:983–992. doi: 10.1167/iovs.14-15859.
    1. Zagoura D.S., Roubelakis M.G., Bitsika V., Trohatou O., Pappa K.I., Kapelouzou A., Antsaklis A., Anagnou N.P. Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure. Gut. 2012;61:894–906. doi: 10.1136/gutjnl-2011-300908.
    1. Xiong L.L., Li Y., Shang F.F., Chen S.W., Chen H., Ju S.M., Zou Y., Tian H.L., Wang T.H., Luo C.Z., et al. Chondroitinase administration and pcDNA3.1-BDNF-BMSC transplantation promote motor functional recovery associated with NGF expression in spinal cord-transected rat. Spinal Cord. 2016;54:1088–1095. doi: 10.1038/sc.2016.55.
    1. Zanotti L., Angioni R., Calì B., Soldani C., Ploia C., Moalli F., Gargesha M., D’Amico G., Elliman S., Tedeschi G., et al. Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1. Leukemia. 2016;30:1143–1154. doi: 10.1038/leu.2016.33.
    1. Li L., Li L., Zhang Z., Jiang Z. Hypoxia promotes bone marrow-derived mesenchymal stem cell proliferation through apelin/APJ/autophagy pathway. Acta Biochim. Biophys. Sin. (Shanghai) 2015;47:362–367. doi: 10.1093/abbs/gmv014.
    1. Jakovljevic J., Harrell C.R., Fellabaum C., Arsenijevic A., Jovicic N., Volarevic V. Modulation of autophagy as new approach in mesenchymal stem cell-based therapy. Biomed. Pharmacother. 2018;104:404–410. doi: 10.1016/j.biopha.2018.05.061.
    1. Zhang Y., Hao Z., Wang P., Xia Y., Wu J., Xia D., Fang S., Xu S. Exosomes from human umbilical cord mesenchymal stem cells enhance fracture healing through HIF-1α-mediated promotion of angiogenesis in a rat model of stabilized fracture. Cell. Prolif. 2019;52:e12570. doi: 10.1111/cpr.12570.
    1. Tao H., Han Z., Han Z.C., Li Z. Proangiogenic Features of Mesenchymal Stem Cells and Their Therapeutic Applications. Stem Cells Int. 2016;2016 doi: 10.1155/2016/1314709.
    1. Eiró N., Sendon-Lago J., Seoane S., Bermúdez M.A., Lamelas M.L., Garcia-Caballero T., Schneider J., Perez-Fernandez R., Vizoso F.J. Potential therapeutic effect of the secretome from human uterine cervical stem cells against both cancer and stromal cells compared with adipose tissue stem cells. Oncotarget. 2014;5:10692–10708. doi: 10.18632/oncotarget.2530.
    1. Huang B., Cheng X., Wang H., Huang W., la Ga Hu Z., Wang D., Zhang K., Zhang H., Xue Z., Da Y., et al. Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. J. Transl. Med. 2016;14 doi: 10.1186/s12967-016-0792-1.
    1. Mansurov N., Chen W.C.W., Awada H., Huard J., Wang Y., Saparov A. A controlled release system for simultaneous delivery of three human perivascular stem cell-derived factors for tissue repair and regeneration. J. Tissue. Eng. Regen. Med. 2018;12:e1164–e1172. doi: 10.1002/term.2451.
    1. Milosavljevic N., Gazdic M., Simovic Markovic B., Arsenijevic A., Nurkovic J., Dolicanin Z., Djonov V., Lukic M.L., Volarevic V. Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells. Liver Transpl. 2017;23:1040–1050. doi: 10.1002/lt.24784.
    1. Tuncer C., Oo Y.H., Murphy N., Adams D.H., Lalor P.F. The regulation of T-cell recruitment to the human liver during acute liver failure. Liver Int. 2013;33:852–863. doi: 10.1111/liv.12182.
    1. Gazdic M., Simovic Markovic B., Vucicevic L., Nikolic T., Djonov V., Arsenijevic N., Trajkovic V., Lukic M.L., Volarevic V. Mesenchymal stem cells protect from acute liver injury by attenuating hepatotoxicity of liver natural killer T cells in an inducible nitric oxide synthase- and indoleamine 2,3-dioxygenase-dependentmanner. J. Tissue Eng. Regen. Med. 2018;12:e1173–e1185. doi: 10.1002/term.2452.
    1. Fabre T., Molina M.F., Soucy G., Goulet J.P., Willems B., Villeneuve J.P., Bilodeau M., Shoukry N.H. Type 3 cytokines IL-17A and IL-22 drive TGF-β-dependent liver fibrosis. Sci. Immunol. 2018;3 doi: 10.1126/sciimmunol.aar7754.
    1. Fabre T., Kared H., Friedman S.L., Shoukry N.H. IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner. J. Immunol. 2014;193:3925–3933. doi: 10.4049/jimmunol.1400861.
    1. Owen A., Newsome P.N. Mesenchymal stromal cell therapy in liver disease: Opportunities and lessons to be learnt? Am. J. Physiol. Gastrointest. Liver Physiol. 2015;309:G791–G800. doi: 10.1152/ajpgi.00036.2015.
    1. Li T., Yan Y., Wang B., Qian H., Zhang X., Shen L., Wang M., Zhou Y., Zhu W., Li W., Xu W. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22:845–854. doi: 10.1089/scd.2012.0395.
    1. Tan C.Y., Lai R.C., Wong W., Dan Y.Y., Lim S.K., Ho H.K. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res. Ther. 2014;5 doi: 10.1186/scrt465.
    1. Hyun J., Wang S., Kim J., Kim G.J., Jung Y. MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells. Sci. Rep. 2015;5 doi: 10.1038/srep14135.
    1. Morrison T.J., Jackson M.V., Cunningham E.K., Kissenpfennig A., McAuley D.F., O’Kane C.M., Krasnodembskaya A.D. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am. J. Respir. Crit. Care Med. 2017;196:1275–1286. doi: 10.1164/rccm.201701-0170OC.
    1. Cruz F.F., Borg Z.D., Goodwin M., Sokocevic D., Wagner D.E., Coffey A., Antunes M., Robinson K.L., Mitsialis S.A., Kourembanas S., et al. Systemic Administration of Human Bone Marrow-Derived Mesenchymal Stromal Cell Extracellular Vesicles Ameliorates Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation in Immunocompetent Mice. Stem Cells Transl. Med. 2015;4:1302–1316. doi: 10.5966/sctm.2014-0280.
    1. De Castro L.L., Xisto D.G., Kitoko J.Z., Cruz F.F., Olsen P.C., Redondo P.A.G., Ferreira T.P.T., Weiss D.J., Martins M.A., Morales M.M., et al. Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma. Stem Cell Res. Ther. 2017;8 doi: 10.1186/s13287-017-0600-8.
    1. Du Y.M., Zhuansun Y.X., Chen R., Lin L., Lin Y., Li J.G. Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma. Exp. Cell Res. 2018;363:114–120. doi: 10.1016/j.yexcr.2017.12.021.
    1. Chen X., Shi C., Cao H., Chen L., Hou J., Xiang Z., Hu K., Han X. The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. Cell Death Dis. 2018;9 doi: 10.1038/s41419-018-0692-9.
    1. Xu S., Liu C., Ji H.L. Concise Review: Therapeutic Potential of the Mesenchymal Stem Cell Derived Secretome and Extracellular Vesicles for Radiation-Induced Lung Injury: Progress and Hypotheses. Stem Cells Transl. Med. 2019;8:344–354. doi: 10.1002/sctm.18-0038.
    1. Shentu T.P., Huang T.S., Cernelc-Kohan M., Chan J., Wong S.S., Espinoza C.R., Tan C., Gramaglia I., van der Heyde H., Chien S., et al. Thy-1 dependent uptake of mesenchymal stem cell-derived extracellular vesicles blocks myofibroblastic differentiation. Sci. Rep. 2017;7 doi: 10.1038/s41598-017-18288-9.
    1. Seo Y., Kim H.S., Hong I.S. Stem Cell-Derived Extracellular Vesicles as Immunomodulatory Therapeutics. Stem Cells Int. 2019;2019 doi: 10.1155/2019/5126156.
    1. Fujita Y., Kadota T., Araya J., Ochiya T., Kuwano K. Clinical Application of Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapeutics for Inflammatory Lung Diseases. J. Clin. Med. 2018;7:355. doi: 10.3390/jcm7100355.
    1. Chen Y.C., Chang Y.W., Tan K.P., Shen Y.S., Wang Y.H., Chang C.H. Can mesenchymal stem cells and their conditioned medium assist inflammatory chondrocytes recovery? PLoS ONE. 2018;13:e0205563. doi: 10.1371/journal.pone.0205563.
    1. Tofiño-Vian M., Guillén M.I., Pérez Del Caz M.D., Silvestre A., Alcaraz M.J. Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Protective Strategy in Osteoarthritic Chondrocytes. Cell. Physiol. Biochem. 2018;47:11–25. doi: 10.1159/000489739.
    1. Liu Y., Lin L., Zou R., Wen C., Wang Z., Lin F. MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis. Cell Cycle. 2018;17:2411–2422. doi: 10.1080/15384101.2018.1526603.
    1. Liu Y., Zou R., Wang Z., Wen C., Zhang F., Lin F. Exosomal KLF3-AS1 from hMSCs promoted cartilage repair and chondrocyte proliferation in osteoarthritis. Biochem. J. 2018;475:3629–3638. doi: 10.1042/BCJ20180675.
    1. Harrell C.R., Markovic B.S., Fellabaum C., Arsenijevic A., Volarevic V. Mesenchymal stem cell-based therapy of osteoarthritis: Current knowledge and future perspectives. Biomed. Pharmacother. 2019;109:2318–2326. doi: 10.1016/j.biopha.2018.11.099.
    1. Colgan S.P., Eltzschig H.K., Eckle T., Thompson L.F. Physiological roles for ecto-5’-nucleotidase (CD73) Purinergic Signal. 2006;2:351–360. doi: 10.1007/s11302-005-5302-5.
    1. Sun H., Hu S., Zhang Z., Lun J., Liao W., Zhang Z. Expression of exosomal microRNAs during chondrogenic differentiation of human bone mesenchymal stem cells. J. Cell. Biochem. 2019;120:171–181. doi: 10.1002/jcb.27289.
    1. Mao G., Zhang Z., Hu S., Zhang Z., Chang Z., Huang Z., Liao W., Kang Y. Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res. Ther. 2018;9 doi: 10.1186/s13287-018-1004-0.
    1. Zhang L.Q., Zhao G.Z., Xu X.Y., Fang J., Chen J.M., Li J.W., Gao X.J., Hao L.J., Chen Y.Z. Integrin-β1 regulates chondrocyte proliferation and apoptosis through the upregulation of GIT1 expression. Int. J. Mol. Med. 2015;35:1074–1080. doi: 10.3892/ijmm.2015.2114.
    1. Herreros M.D., Garcia-Arranz M., Guadalajara H., De-La-Quintana P., Garcia-Olmo D., FATT Collaborative Group Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: A phase III randomized clinical trial (FATT 1: Fistula Advanced Therapy Trial 1) and long-term evaluation. Dis. Colon. Rectum. 2012;55:762–772. doi: 10.1097/DCR.0b013e318255364a.
    1. Lee W.Y., Park K.J., Cho Y.B., Yoon S.N., Song K.H., Kim D.S., Jung S.H., Kim M., Yoo H.W., Kim I., et al. Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells. 2013;31:2575–2581. doi: 10.1002/stem.1357.
    1. Cho Y.B., Lee W.Y., Park K.J., Kim M., Yoo H.W., Yu C.S. Autologous adipose tissue-derived stem cells for the treatment of Crohn’s fistula: A phase I clinical study. Cell Transplant. 2013;22:279–285. doi: 10.3727/096368912X656045.
    1. Baghaei K., Tokhanbigli S., Asadzadeh H., Nmaki S., Reza Zali M., Hashemi S.M. Exosomes as a novel cell-free therapeutic approach in gastrointestinal diseases. J. Cell Physiol. 2019;234:9910–9926. doi: 10.1002/jcp.27934.
    1. Capitini C.M., Chisti A.A., Mackall C.L. Modulating T-cell homeostasis with IL-7: Preclinical and clinical studies. J. Intern. Med. 2009;266:141–153. doi: 10.1111/j.1365-2796.2009.02085.x.
    1. Ji T., Xu C., Sun L., Yu M., Peng K., Qiu Y., Xiao W., Yang H. Aryl Hydrocarbon Receptor Activation Down-Regulates IL-7 and Reduces Inflammation in a Mouse Model of DSS-Induced Colitis. Dig. Dis. Sci. 2015;60:1958–1966. doi: 10.1007/s10620-015-3632-x.
    1. Wu Y., Qiu W., Xu X., Kang J., Wang J., Wen Y., Tang X., Yan Y., Qian H., Zhang X., et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate inflammatory bowel disease in mice through ubiquitination. Am. J. Transl. Res. 2018;10:2026–2036.
    1. Lazar E., Benedek T., Korodi S., Rat N., Lo J., Benedek I. Stem cell-derived exosomes-an emerging tool for myocardial regeneration. World J. Stem Cells. 2018;10:106–115. doi: 10.4252/wjsc.v10.i8.106.
    1. Ju C., Shen Y., Ma G., Liu Y., Cai J., Kim I.M., Weintraub N.L., Liu N., Tang Y. Transplantation of Cardiac Mesenchymal Stem Cell-Derived Exosomes Promotes Repair in Ischemic Myocardium. J. Cardiovasc. Transl. Res. 2018;11:420–428. doi: 10.1007/s12265-018-9822-0.
    1. 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 doi: 10.1161/JAHA.115.002856.
    1. Liu L., Jin X., Hu C.F., Li R., Zhou Z., Shen C.X. Exosomes Derived from Mesenchymal Stem Cells Rescue Myocardial Ischaemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy Via AMPK and Akt Pathways. Cell. Physiol. Biochem. 2017;43:52–68. doi: 10.1159/000480317.
    1. Cui X., He Z., Liang Z., Chen Z., Wang H., Zhang J. Exosomes From Adipose-derived Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Wnt/β-Catenin Signaling Pathway. J. Cardiovasc. Pharmacol. 2017;70:225–231. doi: 10.1097/FJC.0000000000000507.
    1. Zhu L.P., Tian T., Wang J.Y., He J.N., Chen T., Pan M., Xu L., Zhang H.X., Qiu X.T., Li C.C., et al. Hypoxia-elicited mesenchymal stem cell-derived exosomes facilitates cardiac repair through miR-125b-mediated prevention of cell death in myocardial infarction. Theranostics. 2018;8:6163–6177. doi: 10.7150/thno.28021.
    1. Zhu J., Lu K., Zhang N., Zhao Y., Ma Q., Shen J., Lin Y., Xiang P., Tang Y., Hu X., et al. Myocardial reparative functions of exosomes from mesenchymal stem cells are enhanced by hypoxia treatment of the cells via transferring microRNA-210 in an nSMase2-dependent way. Artif. Cells Nanomed. Biotechnol. 2018;46:1659–1670. doi: 10.1080/21691401.2017.1388249.
    1. Suzuki E., Fujita D., Takahashi M., Oba S., Nishimatsu H. Stem cell-derived exosomes as a therapeutic tool for cardiovascular disease. World. J. Stem Cells. 2016;8:297–305. doi: 10.4252/wjsc.v8.i9.297.
    1. Dimova I., Karthik S., Makanya A., Hlushchuk R., Semela D., Volarevic V., Djonov V. SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception. J. Cell Mol. Med. 2019 doi: 10.1111/jcmm.14269.
    1. Gong X.H., Liu H., Wang S.J., Liang S.W., Wang G.G. Exosomes derived from SDF1-overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction. J. Cell Physiol. 2019 doi: 10.1002/jcp.28070.
    1. Ma T., Chen Y., Chen Y., Meng Q., Sun J., Shao L., Yu Y., Huang H., Hu Y., Yang Z., et al. MicroRNA-132, Delivered by Mesenchymal Stem Cell-Derived Exosomes, Promote Angiogenesis in Myocardial Infarction. Stem Cells Int. 2018;2018 doi: 10.1155/2018/3290372.
    1. Huang P., Tian X., Li Q., Yang Y. New strategies for improving stem cell therapy in ischemic heart disease. Heart Fail. Rev. 2016;21:737–752. doi: 10.1007/s10741-016-9576-1.
    1. Parikh M., Raj P., Yu L., Stebbing J.A., Prashar S., Petkau J.C., Tappia P.S., Pierce G.N., Siow Y.L., Brown D., et al. Ginseng Berry Extract Rich in Phenolic Compounds Attenuates Oxidative Stress but not Cardiac Remodeling post Myocardial Infarction. Int. J. Mol. Sci. 2019;20:983. doi: 10.3390/ijms20040983.
    1. Sun X., Shan A., Wei Z., Xu B. Intravenous mesenchymal stem cell-derived exosomes ameliorate myocardial inflammation in the dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 2018;503:2611–2618. doi: 10.1016/j.bbrc.2018.08.012.
    1. Mead B., Tomarev S. Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Transl. Med. 2017;6:1273–1285. doi: 10.1002/sctm.16-0428.
    1. Mead B., Ahmed Z., Tomarev S. Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in a Genetic DBA/2J Mouse Model of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59:5473–5480. doi: 10.1167/iovs.18-25310.
    1. Mead B., Amaral J., Tomarev S. Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in Rodent Models of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59:702–714. doi: 10.1167/iovs.17-22855.
    1. Shigemoto-Kuroda T., Oh J.Y., Kim D.K., Jeong H.J., Park S.Y., Lee H.J., Park J.W., Kim T.W., An S.Y., Prockop D.J., 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: 10.1016/j.stemcr.2017.04.008.
    1. Gayton J.L. Etiology, prevalence, and treatment of dry eye disease. Clin. Ophthalmol. 2009;3:405–412. doi: 10.2147/OPTH.S5555.
    1. De Paiva C.S., Chotikavanich S., Pangelinan S.B., Pitcher J.D., 3rd, Fang B., Zheng X., Ma P., Farley W.J., Siemasko K.F., Niederkorn J.Y., et al. IL-17 disrupts corneal barrier following desiccating stress. Mucosal. Immunol. 2009;2:243–253. doi: 10.1038/mi.2009.5.
    1. Lu P., Li L., Liu G., Zhang X., Mukaida N. Enhanced experimental corneal neovascularization along with aberrant angiogenic factor expression in the absence of IL-1 receptor antagonist. Invest. Ophthalmol. Vis. Sci. 2009;50:4761–4768. doi: 10.1167/iovs.08-2732.
    1. Luz-Crawford P., Djouad F., Toupet K., Bony C., Franquesa M., Hoogduijn M.J., Jorgensen C., Noël D. Mesenchymal Stem Cell-Derived Interleukin 1 Receptor Antagonist Promotes Macrophage Polarization and Inhibits B Cell Differentiation. Stem Cells. 2016;34:483–492. doi: 10.1002/stem.2254.
    1. Yi T., Song S.U. Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications. Arch. Pharm. Res. 2012;35:213–221. doi: 10.1007/s12272-012-0202-z.
    1. Harrell C.R., Fellabaum C., Simovic Markovic B., Arsenijevic A., Volarevic V. Therapeutic potential of “Exosomes derived Multiple Allogeneic Proteins Paracrine Signaling: Exosomes d-MAPPS” is based on the effects of exosomes, immunosuppressive and trophic factors. Ser. J. Exp. Clin. Res. 2018 doi: 10.2478/sjecr-2018-0032.
    1. Coulson-Thomas V.J., Caterson B., Kao W.W. Transplantation of human umbilical mesenchymal stem cells cures the corneal defects of mucopolysaccharidosis VII mice. Stem Cells. 2013;31:2116–2126. doi: 10.1002/stem.1481.
    1. Xin H., Li Y., Cui Y., Yang J.J., Zhang Z.G., Chopp M. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cereb. Blood Flow Metab. 2013;33:1711–1715. doi: 10.1038/jcbfm.2013.152.
    1. Li D., Zhang P., Yao X., Li H., Shen H., Li X., Wu J., Lu X. Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury. Front. Neurosci. 2018;12 doi: 10.3389/fnins.2018.00845.
    1. Huang J.H., Yin X.M., Xu Y., Xu C.C., Lin X., Ye F.B., Cao Y., Lin F.Y. Systemic Administration of Exosomes Released from Mesenchymal Stromal Cells Attenuates Apoptosis, Inflammation, and Promotes Angiogenesis after Spinal Cord Injury in Rats. J. Neurotrauma. 2017;34:3388–3396. doi: 10.1089/neu.2017.5063.
    1. Sun G., Li G., Li D., Huang W., Zhang R., Zhang H., Duan Y., Wang B. hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation. Mater. Sci. Eng. C. Mater. Biol. Appl. 2018;89:194–204. doi: 10.1016/j.msec.2018.04.006.
    1. Wang L., Pei S., Han L., Guo B., Li Y., Duan R., Yao Y., Xue B., Chen X., Jia Y. Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury. Cell Physiol. Biochem. 2018;50:1535–1559. doi: 10.1159/000494652.
    1. Lankford K.L., Arroyo E.J., Nazimek K., Bryniarski K., Askenase P.W., Kocsis J.D. Intravenously delivered mesenchymal stem cell-derived exosomes target M2-type macrophages in the injured spinal cord. PLoS ONE. 2018;13:e0190358. doi: 10.1371/journal.pone.0190358.
    1. Shiue S.J., Rau R.H., Shiue H.S., Hung Y.W., Li Z.X., Yang K.D., Cheng J.K. Mesenchymal stem cell exosomes as a cell-free therapy for nerve injury-induced pain in rats. Pain. 2019;160:210–223. doi: 10.1097/j.pain.0000000000001395.
    1. Lu Y., Zhou Y., Zhang R., Wen L., Wu K., Li Y., Yao Y., Duan R., Jia Y. Bone Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote Recovery Following Spinal Cord Injury via Improvement of the Integrity of the Blood-Spinal Cord Barrier. Front. Neurosci. 2019;13 doi: 10.3389/fnins.2019.00209.
    1. Katagiri W., Osugi M., Kawai T., Hibi H. First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. Head Face Med. 2016;12 doi: 10.1186/s13005-016-0101-5.
    1. Fukuoka H., Suga H. Hair regeneration treatment using adipose-derived stem cell conditioned medium: Follow-up with trichograms. Eplasty. 2015;15:e10.
    1. Shin H., Ryu H.H., Kwon O., Park B.S., Jo S.J. Clinical use of conditioned media of adipose tissue-derived stem cells in female pattern hair loss: A retrospective case series study. Int. J. Dermatol. 2015;54:730–735. doi: 10.1111/ijd.12650.
    1. Kordelas L., Rebmann V., Ludwig A.K., Radtke S., Ruesing J., Doeppner T.R., Epple M., Horn P.A., Beelen D.W., Giebel B. MSC-derived exosomes: A novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28:970–973. doi: 10.1038/leu.2014.41.
    1. Ringden O., Le Blanc K. Mesenchymal stem cells for treatment of acute and chronic graft-versus-host disease, tissue toxicity and hemorrhages. Best Pract. Res. Clin. Haematol. 2011;24:65–72. doi: 10.1016/j.beha.2011.01.003.
    1. Berglund A.K., Schnabel L.V. Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies. Equine Vet. J. 2017;49:539–544. doi: 10.1111/evj.12647.
    1. Berglund A.K., Fortier L.A., Antczak D.F., Schnabel L.V. Immunoprivileged no more: Measuring the immunogenicity of allogeneic adult mesenchymal stem cells. Stem Cell Res. Ther. 2017;8:288. doi: 10.1186/s13287-017-0742-8.
    1. Pezzanite L.M., Fortier L.A., Antczak D.F., Cassano J.M., Brosnahan M.M., Miller D., Schnabel L.V. Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo. Stem Cell Res. Ther. 2015;6:54. doi: 10.1186/s13287-015-0053-x.
    1. Griffin M.D., Ryan A.E., Alagesan S., Lohan P., Treacy O., Ritter T. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: What have we learned so far? Immunol. Cell Biol. 2013;91:40–51. doi: 10.1038/icb.2012.67.
    1. Liu Q., Rojas-Canales D.M., Divito S.J., Shufesky W.J., Stolz D.B., Erdos G., Sullivan M.L., Gibson G.A., Watkins S.C., Larregina A.T., et al. Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J. Clin. Invest. 2016;126:2805–2820. doi: 10.1172/JCI84577.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren