Abstract
Exosomes as well as other extracellular vesicles (EVs) play an important role in cell–cell communication. Recently, EVs have been used as a platform for cellular therapy for conditions such as degenerative diseases. EVs were demonstrated to stimulate angiogenesis, cell proliferation, and immune modulation. This study aims to determine the factors, particularly proinflammatory factors, can stimulate adipose-derived mesenchymal stem cells (ADSCs) and umbilical cord-derived mesenchymal stem cells (UC-MSCs) to generate exosomes and EVs. ADSCs and UC-MSCs were isolated, proliferated, and characterized from adipose tissue and umbilical cord tissue, respectively, according to previously published protocols. The isolated MSCs were treated in vitro with proinflammatory cytokines (including TNF-alpha and IFN-gamma) for 24, 48, and 96 h at three different concentrations (5, 10, and 20 ng/mL). The number count of generated EVs/exosomes was determined by flow cytometry; additionally, exosomes were assessed for amount of nucleic acids and for morphology (via transmission electron microscopy). The results showed that TNF-alpha and IFN-gamma stimulate MSCs from both umbilical cord and adipose tissue to produce a greater number of exosomes and EVs. However, longer culture with proinflammatory cytokines (>96 h) led to a reduction of EV production compared to shorter times (24 or 48 h). Our observations show that EVs are effective cargos for delivery of information in cell–cell communication and are modulated by proinflammatory cytokines in a dose-dependent manner.
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References
Baglio SR, Pegtel DM, Baldini N (2012) Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol 3:359
Biancone L, Bruno S, Deregibus MC, Tetta C, Camussi G (2012) Therapeutic potential of mesenchymal stem cell-derived microvesicles. Nephrol Dial Transplant 27:3037–3042
Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, Tetta C, Camussi G (2012) Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One 7:e33115
Chen L, Xiang B, Wang X, Xiang C (2017) Exosomes derived from human menstrual blood-derived stem cells alleviate fulminant hepatic failure. Stem Cell Res Ther 8:9
Deng M, Xiao H, Zhang H, Peng H, Yuan H, Xu Y, Zhang G, Hu Z (2017) Mesenchymal stem cell-derived extracellular vesicles ameliorates hippocampal synaptic impairment after transient global ischemia. Front Cell Neurosci 11:205
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
Doeppner TR, Herz J, Gorgens A, Schlechter J, Ludwig AK, Radtke S, de Miroschedji K, Horn PA, Giebel B, Hermann DM (2015) Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 4:1131–1143
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining mulipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317
Eirin A, Riester SM, Zhu XY, Tang H, Evans JM, O'Brien D, van Wijnen AJ, Lerman LO (2014) MicroRNA and mRNA cargo of extracellular vesicles from porcine adipose tissue-derived mesenchymal stem cells. Gene 551:55–64
Feng Y, Huang W, Wani M, Yu X, Ashraf M (2014) Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One 9:e88685
Haga H, Yan IK, Takahashi K, Matsuda A, Patel T (2017) Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice. Stem Cells Transl Med 6:1262–1272
Hu B, Chen S, Zou M, He Z, Shao S, Liu B (2016) Effect of extracellular vesicles on neural functional recovery and immunologic suppression after rat cerebral apoplexy. Cell Physiol Biochem 40:155–162
Kim DK, Nishida H, An SY, Shetty AK, Bartosh TJ, Prockop DJ (2016) Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci U S A 113:170–175
Koch M, Lemke A, Lange C (2015) Extracellular vesicles from MSC modulate the immune response to renal allografts in a MHC disparate rat model. Stem Cells Int 2015:486141
Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, Epple M, Horn PA, Beelen DW, Giebel B (2014) MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28:970–973
Kumar L, Verma S, Vaidya B, Gupta V (2015) Exosomes: natural carriers for siRNA delivery. Curr Pharm Des 21:4556–4565
Kwon YW, Heo SC, Jeong GO, Yoon JW, Mo WM, Lee MJ, Jang IH, Kwon SM, Lee JS, Kim JH (2013) Tumor necrosis factor-alpha-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis. Biochim Biophys Acta 1832:2136–2144
Lin KC, Yip HK, Shao PL, Wu SC, Chen KH, Chen YT, Yang CC, Sun CK, Kao GS, Chen SY et al (2016) Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia-reperfusion injury. Int J Cardiol 216:173–185
Lo Sicco C, Reverberi D, Balbi C, Ulivi V, Principi E, Pascucci L, Becherini P, Bosco MC, Varesio L, Franzin C et al (2017) Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med 6:1018–1028
Lu Z, Wang G, Dunstan CR, Chen Y, Lu WY, Davies B, Zreiqat H (2013) Activation and promotion of adipose stem cells by tumour necrosis factor-alpha preconditioning for bone regeneration. J Cell Physiol 228:1737–1744
Ma J, Zhao Y, Sun L, Sun X, Zhao X, Sun X, Qian H, Xu W, Zhu W (2016) Exosomes derived from Akt-modified human umbilical cord mesenchymal stem cells improve cardiac regeneration and promote angiogenesis via activating platelet-derived growth factor D. Stem Cells Transl Med 6(1):51–59
Madrigal M, Rao KS, Riordan NH (2014) A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med 12:260
Nassar W, El-Ansary M, Sabry D, Mostafa MA, Fayad T, Kotb E, Temraz M, Saad AN, Essa W, Adel H (2016) Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res 20:21
Nong K, Wang W, Niu X, Hu B, Ma C, Bai Y, Wu B, Wang Y, Ai K (2016) Hepatoprotective effect of exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats. Cytotherapy 18:1548–1559
Ophelders DR, Wolfs TG, Jellema RK, Zwanenburg A, Andriessen P, Delhaas T, Ludwig AK, Radtke S, Peters V, Janssen L et al (2016) Mesenchymal stromal cell-derived extracellular vesicles protect the fetal brain after hypoxia-ischemia. Stem Cells Transl Med 5:754–763
Ramos T, Sánchez-Abarca LI, Muntión S, Preciado S, Puig N, López-Ruano G, Hernández-Hernández Á, Redondo A, Ortega R, Rodríguez C et al (2016) MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry. Cell Commun Signal 14:2
Ranghino A, Bruno S, Bussolati B, Moggio A, Dimuccio V, Tapparo M, Biancone L, Gontero P, Frea B, Camussi G (2017) The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury. Stem Cell Res Ther 8:24
Rani S, Ryan AE, Griffin MD, Ritter T (2015) Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther 23:812–823
Shao L, Zhang Y, Lan B, Wang J, Zhang Z, Zhang L, Xiao P, Meng Q, Geng YJ, Yu XY et al (2017) MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. Biomed Res Int 2017:4150705
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
Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z (2015) Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem 37:2415–2424
Vallabhaneni KC, Penfornis P, Dhule S, Guillonneau F, Adams KV, Mo YY, Xu R, Liu Y, Watabe K, Vemuri MC et al (2015) Extracellular vesicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA, proteins, and metabolites. Oncotarget 6:4953–4967
Van Pham P, Truong NC, Le PT, Tran TD, Vu NB, Bui KH, Phan NK (2016a) Isolation and proliferation of umbilical cord tissue derived mesenchymal stem cells for clinical applications. Cell Tissue Bank 17:289–302
Van Pham P, Vu NB, Phan NK (2016b) Umbilical cord-derived stem cells (MODULATISTTM) show strong immunomodulation capacity compared to adipose tissue-derived or bone marrow-derived mesenchymal stem cells. Biomed Res Ther 3:687–696
Van Pham P, Vu NB, Phan NL-C, Le DM, Truong NC, Truong NH, Bui KH-T, Phan NK (2014) Good manufacturing practice-compliant isolation and culture of human adipose derived stem cells. Biomed Res Ther 1:21
Xing J, Hou T, Jin H, Luo F, Change Z, Li Z, Xie Z, Xu J (2014) Inflammatory microenvironment changes the secretory profile of mesenchymal stem cells to recruit mesenchymal stem cells. Cell Physiol Biochem 33:905–919
Yu B, Shao H, Su C, Jiang Y, Chen X, Bai L, Zhang Y, Li Q, Zhang X, Li X (2016) Exosomes derived from MSCs ameliorate retinal laser injury partially by inhibition of MCP-1. Sci Rep 6:34562
Zhang Y, Chopp M, Zhang ZG, Katakowski M, Xin H, Qu C, Ali M, Mahmood A, Xiong Y (2016) Systemic administration of cell-free exosomes generated by human bone marrow derived mesenchymal stem cells cultured under 2D and 3D conditions improves functional recovery in rats after traumatic brain injury. Neurochem Int 111:69–81
Zhao Y, Sun X, Cao W, Ma J, Sun L, Qian H, Zhu W, Xu W (2015) Exosomes derived from human umbilical cord mesenchymal stem cells relieve acute myocardial ischemic injury. Stem Cells Int 2015:761643
Zhou Y, Xu H, Xu W, Wang B, Wu H, Tao Y, Zhang B, Wang M, Mao F, Yan Y et al (2013) Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res Ther 4:34
Zou X, Gu D, Xing X, Cheng Z, Gong D, Zhang G, Zhu Y (2016) Human mesenchymal stromal cell-derived extracellular vesicles alleviate renal ischemic reperfusion injury and enhance angiogenesis in rats. Am J Transl Res 8:4289–4299
Zou X, Zhang G, Cheng Z, Yin D, Du T, Ju G, Miao S, Liu G, Lu M, Zhu Y (2014) Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther 5:40
Acknowledgment
This research was funded and supported by Vietnam National University Ho Chi Minh City via project TX2017-18-02, by Ministry of Science and Technology, Vietnam under grant number DM.10.DA/15; by Fostering Innovation through Research, Science and Technology, Vietnam via project 15/FIRST/2a/SCI.
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Van Pham, P., Vu, N.B., Bui, K.HT., Pham, L.H. (2018). Proinflammatory Cytokines Significantly Stimulate Extracellular Vesicle Production by Adipose-Derived and Umbilical Cord-Derived Mesenchymal Stem Cells. In: Pham, P. (eds) Stem Cell Drugs - A New Generation of Biopharmaceuticals. Stem Cells in Clinical Applications. Springer, Cham. https://doi.org/10.1007/978-3-319-99328-7_5
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DOI: https://doi.org/10.1007/978-3-319-99328-7_5
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