Effects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases

Author(s): Wenjie Zheng, Yumin Yang, Russel Clive Sequeira, Colin E. Bishop, Anthony Atala, Zhifeng Gu*, Weixin Zhao*.

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 5 , 2019

Become EABM
Become Reviewer


Therapeutic effects of Mesenchymal Stem/Stromal Cells (MSCs) transplantation have been observed in various disease models. However, it is thought that MSCs-mediated effects largely depend on the paracrine manner of secreting cytokines, growth factors, and Extracellular Vesicles (EVs). Similarly, MSCs-derived EVs also showed therapeutic benefits in various liver diseases through alleviating fibrosis, improving regeneration of hepatocytes, and regulating immune activity. This review provides an overview of the MSCs, their EVs, and their therapeutic potential in treating various liver diseases including liver fibrosis, acute and chronic liver injury, and Hepatocellular Carcinoma (HCC). More specifically, the mechanisms by which MSC-EVs induce therapeutic benefits in liver diseases will be covered. In addition, comparisons between MSCs and their EVs were also evaluated as regenerative medicine against liver diseases. While the mechanisms of action and clinical efficacy must continue to be evaluated and verified, MSCs-derived EVs currently show tremendous potential and promise as a regenerative medicine treatment for liver disease in the future.

Keywords: Mesenchymal stem/stromal cells, extracellular vesicles, liver diseases, fibrosis, hepatocellular carcinoma, regenerative medicine.

Marcellin P, Kutala BK. Liver diseases: A major, neglected global public health problem requiring urgent actions and large-scale screening. Liver Int 2018; 38(Suppl. 1): 2-6.
Wang FS, Fan JG, Zhang Z, Gao B, Wang HY. The global burden of liver disease: the major impact of China. Hepatology 2014; 60(6): 2099-108.
Toniutto P, Zanetto A, Ferrarese A, Burra P. Current challenges and future directions for liver transplantation. Liver Int 2017; 37(3): 317-27.
Kobolak J, Dinnyes A, Memic A, Khademhosseini A, Mobasheri A. Mesenchymal stem cells: Identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche. Methods 2016; 99: 62-8.
Kariminekoo S, Movassaghpour A, Rahimzadeh A, Talebi M, Shamsasenjan K, Akbarzadeh A. Implications of mesenchymal stem cells in regenerative medicine. Artif Cells Nanomed Biotechnol 2016; 44(3): 749-57.
Ebrahim N, Ahmed IA, Hussien NI, et al. Mesenchymal Stem Cell-Derived Exosomes Ameliorated Diabetic Nephropathy by Autophagy Induction through the mTOR Signaling Pathway. Cells 2018; 7(12)
Ju C, Shen Y, Ma G, et al. Transplantation of cardiac mesenchymal stem cell-derived exosomes promotes repair in ischemic myocardium. J Cardiovasc Transl Res 2018; 11(5): 420-8.
Fiore EJ, Dominguez LM, Bayo J, Garcia MG, Mazzolini GD. Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol 2018; 24(23): 2427-40.
Willis GR, Fernandez-Gonzalez A, Reis M, Mitsialis SA, Kourembanas S. Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension? Int J Mol Sci 2018; 19(9): pii: E2534
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(6)e346
Wang J, Cen P, Chen J, et al. Role of mesenchymal stem cells, their derived factors, and extracellular vesicles in liver failure. Stem Cell Res Ther 2017; 8(1): 137.
Yang N, Li S, Li G, et al. The role of extracellular vesicles in mediating progression, metastasis and potential treatment of hepatocellular carcinoma. Oncotarget 2017; 8(2): 3683-95.
Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 1966; 16(3): 381-90.
Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24(5): 1294-301.
Zhang Y, Li CD, Jiang XX, Li HL, Tang PH, Mao N. Comparison of mesenchymal stem cells from human placenta and bone marrow. Chin Med J (Engl) 2004; 117(6): 882-7.
Perry BC, Zhou D, Wu X, et al. Collection, cryopreservation, and characterization of human dental pulp-derived mesenchymal stem cells for banking and clinical use. Tissue Eng Part C Methods 2008; 14(2): 149-56.
Lis R, Touboul C, Mirshahi P, et al. Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12. Int J Cancer 2011; 128(3): 715-25.
Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 2006; 8(4): 315-7.
Bourin P, Bunnell BA, Casteilla L, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: A joint statement of the international federation for adipose therapeutics and science (IFATS) and the international society for cellular therapy (ISCT). Cytotherapy 2013; 15(6): 641-8.
Terai S, Ishikawa T, Omori K, et al. Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells 2006; 24(10): 2292-8.
Fang B, Shi M, Liao L, Yang S, Liu Y, Zhao RC. Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice. Transplantation 2004; 78(1): 83-8.
Parekkadan B, van Poll D, Megeed Z, et al. Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun 2007; 363(2): 247-52.
Jang YO, Jun BG, Baik SK, Kim MY, Kwon SO. Inhibition of hepatic stellate cells by bone marrow-derived mesenchymal stem cells in hepatic fibrosis. Clin Mol Hepatol 2015; 21(2): 141-9.
Milosavljevic N, Gazdic M, Simovic Markovic B, et al. Mesenchymal stem cells attenuate liver fibrosis by suppressing Th17 cells - an experimental study. Transpl Int 2018; 31(1): 102-15.
Seo KW, Sohn SY, Bhang DH, Nam MJ, Lee HW, Youn HY. Therapeutic effects of hepatocyte growth factor-overexpressing human umbilical cord blood-derived mesenchymal stem cells on liver fibrosis in rats. Cell Biol Int 2014; 38(1): 106-16.
Lai L, Chen J, Wei X, et al. Transplantation of MSCs Overexpressing HGF into a Rat Model of Liver Fibrosis. Mol Imaging Biol 2016; 18(1): 43-51.
Fiore EJ, Bayo JM, Garcia MG, et al. Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice. Stem Cells Dev 2015; 24(6): 791-801.
Fiore E, Malvicini M, Bayo J, et al. Involvement of hepatic macrophages in the antifibrotic effect of IGF-I-overexpressing mesenchymal stromal cells. Stem Cell Res Ther 2016; 7(1): 172.
Jang YO, Cho MY, Yun CO, et al. Effect of Function-Enhanced Mesenchymal Stem Cells Infected With Decorin-Expressing Adenovirus on Hepatic Fibrosis. Stem Cells Transl Med 2016; 5(9): 1247-56.
Wu SP, Yang Z, Li FR, Liu XD, Chen HT, Su DN. Smad7-overexpressing rat BMSCs inhibit the fibrosis of hepatic stellate cells by regulating the TGF-beta1/Smad signaling pathway. Exp Ther Med 2017; 14(3): 2568-76.
Lou G, Yang Y, Liu F, et al. MiR-122 modification enhances the therapeutic efficacy of adipose tissue-derived mesenchymal stem cells against liver fibrosis. J Cell Mol Med 2017; 21(11): 2963-73.
Huang CK, Lee SO, Lai KP, et al. Targeting androgen receptor in bone marrow mesenchymal stem cells leads to better transplantation therapy efficacy in liver cirrhosis. Hepatology 2013; 57(4): 1550-63.
Xuan J, Feng W, An ZT, et al. Anti-TGFbeta-1 receptor inhibitor mediates the efficacy of the human umbilical cord mesenchymal stem cells against liver fibrosis through TGFbeta-1/Smad pathway. Mol Cell Biochem 2017; 429(1-2): 113-22.
Chen L, Zeng W, Yang B, et al. Expression of antisense of microRNA-26a-5p in mesenchymal stem cells increases their therapeutic effects against cirrhosis. Am J Transl Res 2017; 9(3): 1500-8.
Abdel Aziz MT, Khaled HM, El Hindawi A, et al. Effect of mesenchymal stem cells and a novel curcumin derivative on Notch1 signaling in hepatoma cell line. BioMed Res Int 2013; 2013129629
Yulyana Y, Ho IA, Sia KC, et al. Paracrine factors of human fetal MSCs inhibit liver cancer growth through reduced activation of IGF-1R/PI3K/Akt signaling. Mol Ther 2015; 23(4): 746-56.
Abd-Allah SH, Shalaby SM, El-Shal AS, et al. Effect of bone marrow-derived mesenchymal stromal cells on hepatoma. Cytotherapy 2014; 16(9): 1197-206.
Abdel aziz MT, El Asmar MF, Atta HM, et al. Efficacy of mesenchymal stem cells in suppression of hepatocarcinorigenesis in rats: possible role of Wnt signaling. J Exp Clin Cancer Res 2011; 30: 49.
Teshima T, Matsumoto H, Koyama H. Soluble factors from adipose tissue-derived mesenchymal stem cells promote canine hepatocellular carcinoma cell proliferation and invasion. PLoS One 2018; 13(1)e0191539
Jing Y, Han Z, Liu Y, et al. Mesenchymal stem cells in inflammation microenvironment accelerates hepatocellular carcinoma metastasis by inducing epithelial-mesenchymal transition. PLoS One 2012; 7(8)e43272
Han Z, Jing Y, Xia Y, et al. Mesenchymal stem cells contribute to the chemoresistance of hepatocellular carcinoma cells in inflammatory environment by inducing autophagy. Cell Biosci 2014; 4: 22.
Li GC, Zhang HW, Zhao QC, et al. Mesenchymal stem cells promote tumor angiogenesis via the action of transforming growth factor beta1. Oncol Lett 2016; 11(2): 1089-94.
Hernanda PY, Pedroza-Gonzalez A, van der Laan LJ, et al. Tumor promotion through the mesenchymal stem cell compartment in human hepatocellular carcinoma. Carcinogenesis 2013; 34(10): 2330-40.
Yan XL, Jia YL, Chen L, et al. Hepatocellular carcinoma-associated mesenchymal stem cells promote hepatocarcinoma progression: role of the S100A4-miR155-SOCS1-MMP9 axis. Hepatology 2013; 57(6): 2274-86.
Alshareeda AT, Sakaguchi K, Abumaree M, Mohd Zin NK, Shimizu T. The potential of cell sheet technique on the development of hepatocellular carcinoma in rat models. PLoS One 2017; 12(8)e0184004
Gao Y, Yao A, Zhang W, et al. Human mesenchymal stem cells overexpressing pigment epithelium-derived factor inhibit hepatocellular carcinoma in nude mice. Oncogene 2010; 29(19): 2784-94.
Sun XY, Nong J, Qin K, et al. MSC(TRAIL)-mediated HepG2 cell death in direct and indirect co-cultures. Anticancer Res 2011; 31(11): 3705-12.
Knoop K, Schwenk N, Dolp P, et al. Stromal targeting of sodium iodide symporter using mesenchymal stem cells allows enhanced imaging and therapy of hepatocellular carcinoma. Hum Gene Ther 2013; 24(3): 306-16.
Jeong KY, Lee EJ, Kim SJ, Yang SH, Sung YC, Seong J. Irradiation-induced localization of IL-12-expressing mesenchymal stem cells to enhance the curative effect in murine metastatic hepatoma. Int J Cancer 2015; 137(3): 721-30.
Wu N, Zhang YL, Wang HT, et al. Overexpression of hepatocyte nuclear factor 4alpha in human mesenchymal stem cells suppresses hepatocellular carcinoma development through Wnt/beta-catenin signaling pathway downregulation. Cancer Biol Ther 2016; 17(5): 558-65.
Zhang J, Hou L, Wu X, et al. Inhibitory effect of genetically engineered mesenchymal stem cells with Apoptin on hepatoma cells in vitro and in vivo. Mol Cell Biochem 2016; 416(1-2): 193-203.
Li G, Miao F, Zhu J, Chen Y. Antiangiogenesis gene therapy for hepatocellular carcinoma via systemic injection of mesenchymal stem cells engineered to secrete soluble Flt1. Mol Med Rep 2017; 16(5): 5799-806.
Szoor A, Vaidya A, Velasquez MP, et al. T Cell-Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC. Mol Ther Oncolytics 2017; 6: 69-79.
Suk KT, Yoon JH, Kim MY, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial. Hepatology 2016; 64(6): 2185-97.
Jang YO, Kim YJ, Baik SK, et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: A pilot study. Liver Int 2014; 34(1): 33-41.
Xu L, Gong Y, Wang B, et al. Randomized trial of autologous bone marrow mesenchymal stem cells transplantation for hepatitis B virus cirrhosis: Regulation of Treg/Th17 cells. J Gastroenterol Hepatol 2014; 29(8): 1620-8.
Shi M, Zhang Z, Xu R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med 2012; 1(10): 725-31.
Mohamadnejad M, Alimoghaddam K, Bagheri M, et al. Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis. Liver Int 2013; 33(10): 1490-6.
Kantarcioglu M, Demirci H, Avcu F, et al. Efficacy of autologous mesenchymal stem cell transplantation in patients with liver cirrhosis. Turk J Gastroenterol 2015; 26(3): 244-50.
Kharaziha P, Hellstrom PM, Noorinayer B, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: A phase I-II clinical trial. Eur J Gastroenterol Hepatol 2009; 21(10): 1199-205.
Tsuchiya A, Kojima Y, Ikarashi S, et al. Clinical trials using mesenchymal stem cells in liver diseases and inflammatory bowel diseases. Inflamm Regen 2017; 37: 16.
Zhao L, Chen S, Shi X, Cao H, Li L. A pooled analysis of mesenchymal stem cell-based therapy for liver disease. Stem Cell Res Ther 2018; 9(1): 72.
Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 2004; 95(1): 9-20.
Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 2004; 94(5): 678-85.
Gnecchi M, He H, Noiseux N, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J 2006; 20(6): 661-9.
S ELA,Mager I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013; 12(5): 347-57.
Lawson C, Kovacs D, Finding E, Ulfelder E, Luis-Fuentes V. Extracellular Vesicles: Evolutionarily Conserved Mediators of Intercellular Communication. Yale J Biol Med 2017; 90(3): 481-91.
Raposo G, Stoorvogel W. Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol 2013; 200(4): 373-83.
Momen-Heravi F, Balaj L, Alian S, et al. Current methods for the isolation of extracellular vesicles. Biol Chem 2013; 394(10): 1253-62.
Momen-Heravi F, Balaj L, Alian S, et al. Alternative methods for characterization of extracellular vesicles. Front Physiol 2012; 3: 354.
Filipe V, Hawe A, Jiskoot W. Critical evaluation of Nanoparticle Tracking Analysis (NTA) by NanoSight for the measurement of nanoparticles and protein aggregates. Pharm Res 2010; 27(5): 796-810.
Aatonen MT, Ohman T, Nyman TA, Laitinen S, Gronholm M, Siljander PR. Isolation and characterization of platelet-derived extracellular vesicles. J Extracell Vesicles 2014; 3.
Figliolini F, Cantaluppi V, De Lena M, et al. Isolation, characterization and potential role in beta cell-endothelium cross-talk of extracellular vesicles released from human pancreatic islets. PLoS One 2014; 9(7)e102521
Koh W, Sheng CT, Tan B, et al. Analysis of deep sequencing microRNA expression profile from human embryonic stem cells derived mesenchymal stem cells reveals possible role of let-7 microRNA family in downstream targeting of hepatic nuclear factor 4 alpha. BMC Genomics 2010; 11(Suppl. 1): S6.
Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20(5): 1053-67.
Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 2010; 4(3): 214-22.
Kordelas L, Rebmann V, Ludwig AK, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 2014; 28(4): 970-3.
Nassar W, El-Ansary M, Sabry D, et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res 2016; 20: 21.
Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther 2014; 5(3): 76.
Tamura R, Uemoto S, Tabata Y. Immunosuppressive effect of mesenchymal stem cell-derived exosomes on a concanavalin A-induced liver injury model. Inflamm Regen 2016; 36: 26.
Du Y, Li D, Han C, et al. Exosomes from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells (hiPSC-MSCs) protect liver against hepatic ischemia/ reperfusion injury via activating sphingosine kinase and sphingosine-1-phosphate signaling pathway. Cell Physiol Biochem 2017; 43(2): 611-25.
Yan Y, Jiang W, Tan Y, et al. hucMSC Exosome-Derived GPX1 Is Required for the Recovery of Hepatic Oxidant Injury. Mol Ther 2017; 25(2): 465-79.
Damania A, Jaiman D, Teotia AK, Kumar A. Mesenchymal stromal cell-derived exosome-rich fractionated secretome confers a hepatoprotective effect in liver injury. Stem Cell Res Ther 2018; 9(1): 31.
Haga H, Yan IK, Takahashi K, Matsuda A, Patel T. Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice. Stem Cells Transl Med 2017; 6(4): 1262-72.
Haga H, Yan IK, Borrelli DA, et al. Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury. Liver Transpl 2017; 23(6): 791-803.
Mardpour S, Hassani SN, Mardpour S, et al. Extracellular Vesicles Derived from Human Embryonic Stem Cell-MSCs Ameliorate Cirrhosis in Thioacetamide-Induced Chronic Liver Injury. J Cell Physiol 2018; 233(12): 9330-44.
Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev 2013; 22(6): 845-54.
Jiang W, Tan Y, Cai M, et al. Human umbilical cord MSC-derived exosomes suppress the development of CCl4-induced liver injury through antioxidant effect. Stem Cells Int 2018; 20186079642
Lee SJ, Kim KH, Park KK. Mechanisms of fibrogenesis in liver cirrhosis: The molecular aspects of epithelial-mesenchymal transition. World J Hepatol 2014; 6(4): 207-16.
Liu L, Jin X, Hu CF, Li R, Zhou Z, Shen CX. 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(1): 52-68.
Zhu F, Chong Lee Shin OLS, et al. Adipose-derived mesenchymal stem cells employed exosomes to attenuate AKI-CKD transition through tubular epithelial cell dependent Sox9 activation. Oncotarget 2017; 8(41): 70707-26.
Potter DR, Miyazawa BY, Gibb SL, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma. J Trauma Acute Care Surg 2018; 84(2): 245-56.
Nong K, Wang W, Niu X, et al. Hepatoprotective effect of exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats. Cytotherapy 2016; 18(12): 1548-59.
Wu HH, Lee OK. Exosomes from mesenchymal stem cells induce the conversion of hepatocytes into progenitor oval cells. Stem Cell Res Ther 2017; 8(1): 117.
Hyun J, Wang S, Kim J, Kim GJ, Jung Y. MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells. Sci Rep 2015; 5: 14135.
Lindoso RS, Collino F, Vieyra A. Extracellular vesicles as regulators of tumor fate: Crosstalk among cancer stem cells, tumor cells and mesenchymal stem cells. Stem Cell Investig 2017; 4: 75.
Whiteside TL. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin Immunol 2018; 35: 69-79.
Yang Y, Bucan V, Baehre H, von der Ohe J, Otte A, Hass R. Acquisition of new tumor cell properties by MSC-derived exosomes. Int J Oncol 2015; 47(1): 244-52.
Zhang X, Tu H, Yang Y, Fang L, Wu Q, Li J. Mesenchymal stem cell-derived extracellular vesicles: Roles in tumor growth, progression, and drug resistance. Stem Cells Int 2017; 20171758139
Lee JK, Park SR, Jung BK, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One 2013; 8(12)e84256
Reza AM, Choi YJ, Yasuda H, Kim JH. Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells. Sci Rep 2016; 6: 38498.
Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P. Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids 2013; 2e126
Lin R, Wang S, Zhao RC. Exosomes from human adipose-derived mesenchymal stem cells promote migration through Wnt signaling pathway in a breast cancer cell model. Mol Cell Biochem 2013; 383(1-2): 13-20.
Mao J, Liang Z, Zhang B, et al. UBR2 enriched in p53 deficient mouse bone marrow mesenchymal stem cell-exosome promoted gastric cancer progression via Wnt/beta-catenin pathway. Stem Cells 2017; 35(11): 2267-79.
Dong L, Pu Y, Zhang L, et al. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles promote lung adenocarcinoma growth by transferring miR-410. Cell Death Dis 2018; 9(2): 218.
Ono M, Kosaka N, Tominaga N, et al. Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Signal 2014; 7(332): ra63.
Bliss SA, Sinha G, Sandiford OA, et al. Mesenchymal stem cell-derived exosomes stimulate cycling quiescence and early breast cancer dormancy in bone marrow. Cancer Res 2016; 76(19): 5832-44.
Ko SF, Yip HK, Zhen YY, et al. Adipose-derived mesenchymal stem cell exosomes suppress hepatocellular carcinoma growth in a rat model: Apparent diffusion coefficient, natural killer T-cell responses, and histopathological features. Stem Cells Int 2015; 2015853506
Xiao YS, Gao Q, Xu XN, et al. Combination of intratumoral invariant natural killer T cells and interferon-gamma is associated with prognosis of hepatocellular carcinoma after curative resection. PLoS One 2013; 8(8)e70345
Tatsumi T, Takehara T. Impact of natural killer cells on chronic hepatitis C and hepatocellular carcinoma. Hepatol Res 2016; 46(5): 416-22.
Yu M, Li Z. Natural killer cells in hepatocellular carcinoma: Current status and perspectives for future immunotherapeutic approaches. Front Med 2017; 11(4): 509-21.
Lou G, Song X, Yang F, et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol 2015; 8: 122.
Stone ML, Zhao Y, Robert Smith J, et al. Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death. Respir Res 2017; 18(1): 212.
Gregorini M, Corradetti V, Pattonieri EF, et al. Perfusion of isolated rat kidney with mesenchymal stromal cells/extracellular vesicles prevents ischaemic injury. J Cell Mol Med 2017; 21(12): 3381-93.
Sharma J, Hampton JM, Valiente GR, et al. Therapeutic development of mesenchymal stem cells or their extracellular vesicles to inhibit autoimmune-mediated inflammatory processes in systemic lupus erythematosus. Front Immunol 2017; 8: 526.
Ranghino A, Bruno S, Bussolati B, et al. The effects of glomerular and tubular renal progenitors and derived extracellular vesicles on recovery from acute kidney injury. Stem Cell Res Ther 2017; 8(1): 24.
Zhu LL, Huang X, Yu W, Chen H, Chen Y, Dai YT. Transplantation of adipose tissue-derived stem cell-derived exosomes ameliorates erectile function in diabetic rats. Andrologia 2018; 50(2)
Nagaishi K, Mizue Y, Chikenji T, et al. Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep 2016; 6: 34842.
Shao L, Zhang Y, Lan B, et al. MiRNA-sequence indicates that mesenchymal stem cells and exosomes have similar mechanism to enhance cardiac repair. BioMed Res Int 2017; 20174150705
Zou XY, Yu Y, Lin S, et al. Comprehensive miRNA analysis of human umbilical cord-derived mesenchymal stromal cells and extracellular vesicles Kidney Blood Press Res 2018; 43(1):1 52-61
Gouveia de Andrade AV, Bertolino G, Riewaldt J, et al. Extracellular vesicles secreted by bone marrow- and adipose tissue-derived mesenchymal stromal cells fail to suppress lymphocyte proliferation. Stem Cells Dev 2015; 24(11): 1374-6.
Jeong JO, Han JW, Kim JM, et al. Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res 2011; 108(11): 1340-7.
Kusuyama J, Bandow K, Shamoto M, Kakimoto K, Ohnishi T, Matsuguchi T. Low intensity pulsed ultrasound (LIPUS) influences the multilineage differentiation of mesenchymal stem and progenitor cell lines through ROCK-Cot/Tpl2-MEK-ERK signaling pathway. J Biol Chem 2014; 289(15): 10330-44.
Saka Y, Furuhashi K, Katsuno T, et al. Adipose-derived stromal cells cultured in a low-serum medium, but not bone marrow-derived stromal cells, impede xenoantibody production. Xenotransplantation 2011; 18(3): 196-208.
Ancans J. Cell therapy medicinal product regulatory framework in Europe and its application for MSC-based therapy development. Front Immunol 2012; 3: 253.
Confalonieri D, Schwab A, Walles H, Ehlicke F. Advanced therapy medicinal products: A guide for bone marrow-derived MSC application in bone and cartilage tissue engineering. Tissue Eng Part B Rev 2018; 24(2): 155-69.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [442 - 452]
Pages: 11
DOI: 10.2174/1574888X14666190308123714
Price: $58

Article Metrics

PDF: 42