Abstract
The multiple therapeutic effects of bone marrow mesenchymal stem cells (BM-MSCs) have been verified in ischemic and reperfusion diseases. Exosomes are thought to play vital roles in MSCs-related cardioprotective effects. Recently, more and more evidences indicated that apoptosis and fibrosis were crucial pathological mechanisms in cardiac remodeling. Whether MSCs-derived exosomes could regulate cardiac hypertrophy and remodeling need to be explored. Murine BM-MSCs-derived exosomes were isolated by differential gradient centrifugation method. The transverse aortic constriction (TAC) mice model was established to promote cardiac remodeling. Cardiac function and remodeling were assessed via echocardiography and histology analysis. Myocytes apoptosis was determined by TUNEL fluorescence staining. Meanwhile, premature senescence was detected by β-galactosidase (SA-β-gal) staining. Related proteins and mRNA alternation were assessed via western blotting and quantitative reverse transcription polymerase chain reaction, respectively. MSCs-derived exosomes significantly protected myocardium against cardiac hypertrophy, attenuated myocardial apoptosis, and fibrosis and preserved heart function when pressure overload. In cultured myocytes, MSCs-derived exosomes also prevented cell hypertrophy stimulated with angiotensin II. One the other hand, exosomes promoted premature senescence of myofibroblasts vitro, indicating its anti-fibrosis effect in cardiac remodeling. Exosomes protected cardiomyocytes against pathological hypertrophy. It may provide a promising future treatment for heart failure.
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References
Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor EN et al (2013) 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 10(3):301–312. https://doi.org/10.1016/j.scr.2013.01.002
Barile L, Moccetti T, Marban E, Vassalli G (2017) Roles of exosomes in cardioprotection. Eur Heart J 38(18):1372–1379. https://doi.org/10.1093/eurheartj/ehw304
Barry SP, Townsend PA (2010) What causes a broken heart--molecular insights into heart failure. Int Rev Cell Mol Biol 284:113–179. https://doi.org/10.1016/S1937-6448(10)84003-1
Cai B, Tan X, Zhang Y, Li X, Wang X, Zhu J, Wang Y, Yang F, Wang B, Liu Y, Xu C, Pan Z, Wang N, Yang B, Lu Y (2015) Mesenchymal stem cells and cardiomyocytes interplay to prevent myocardial hypertrophy. Stem Cells Transl Med 4(12):1425–1435. https://doi.org/10.5966/sctm.2015-0032
Colombo M, Raposo G, Thery C (2014) Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30:255–289. https://doi.org/10.1146/annurev-cellbio-101512-122326
Hill JA, Olson EN (2008) Cardiac plasticity. N Engl J Med 358(13):1370–1380. https://doi.org/10.1056/NEJMra072139
Hong Y, Cao H, Wang Q, Ye J, Sui L, Feng J, Cai X, Song H, Zhang X, Chen X (2016) MiR-22 may suppress fibrogenesis by targeting TGFbetaR I in cardiac fibroblasts. Cell Physiol Biochem 40(6):1345–1353. https://doi.org/10.1159/000453187
Kelkar AA, Butler J, Schelbert EB, Greene SJ, Quyyumi AA, Bonow RO, Cohen I, Gheorghiade M, Lipinski MJ, Sun W, Luger D, Epstein SE (2015) Mechanisms contributing to the progression of ischemic and nonischemic dilated cardiomyopathy: possible modulating effects of paracrine activities of stem cells. J Am Coll Cardiol 66(18):2038–2047. https://doi.org/10.1016/j.jacc.2015.09.010
Kooijmans SAA, Fliervoet LAL, van der Meel R, Fens M, Heijnen HFG, van Bergen En Henegouwen PMP et al (2016) PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. J Control Release 224:77–85. https://doi.org/10.1016/j.jconrel.2016.01.009
Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire C, Chen JW et al (2014) Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 8(1):483–494. https://doi.org/10.1021/nn404945r
Lai RC, Tan SS, Teh BJ, Sze SK, Arslan F, de Kleijn DP, Choo A, Lim SK (2012) Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics 2012:971907–971914. https://doi.org/10.1155/2012/971907
Li G, Xie J, Chen J, Li R, Wu H, Zhang X, Chen Q, Gu R, Xu B (2017) Syndecan-4 deficiency accelerates the transition from compensated hypertrophy to heart failure following pressure overload. Cardiovasc Pathol 28:74–79. https://doi.org/10.1016/j.carpath.2017.03.008
Li M, Wang N, Zhang J, He HP, Gong HQ, Zhang R, Song TF, Zhang LN, Guo ZX, Cao DS, Zhang TC (2016) MicroRNA-29a-3p attenuates ET-1-induced hypertrophic responses in H9c2 cardiomyocytes. Gene 585(1):44–50. https://doi.org/10.1016/j.gene.2016.03.015
Meyer K, Hodwin B, Ramanujam D, Engelhardt S, Sarikas A (2016) Essential role for premature senescence of Myofibroblasts in myocardial fibrosis. J Am Coll Cardiol 67(17):2018–2028. https://doi.org/10.1016/j.jacc.2016.02.047
Moghaddam AS, Afshari JT, Esmaeili SA, Saburi E, Joneidi Z, Momtazi-Borojeni AA (2019) Cardioprotective microRNAs: lessons from stem cell-derived exosomal microRNAs to treat cardiovascular disease. Atherosclerosis 285:1–9. https://doi.org/10.1016/j.atherosclerosis.2019.03.016
Monguio-Tortajada M, Roura S, Galvez-Monton C, Pujal JM, Aran G, Sanjurjo L et al (2017) Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine. Theranostics 7(2):270–284. https://doi.org/10.7150/thno.16154
Munoz-Espin D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15(7):482–496. https://doi.org/10.1038/nrm3823
Rodrigo SF, van Ramshorst J, Beeres SL, Al Younis I, Dibbets-Schneider P, de Roos A et al (2012) Intramyocardial injection of bone marrow mononuclear cells in chronic myocardial ischemia patients after previous placebo injection improves myocardial perfusion and anginal symptoms: an intra-patient comparison. Am Heart J 164(5):771–778. https://doi.org/10.1016/j.ahj.2012.08.008
Roncarati R, Viviani Anselmi C, Losi MA, Papa L, Cavarretta E, Da Costa Martins P et al (2014) Circulating miR-29a, among other up-regulated microRNAs, is the only biomarker for both hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 63(9):920–927. https://doi.org/10.1016/j.jacc.2013.09.041
Schirone L, Forte M, Palmerio S, Yee D, Nocella C, Angelini F, Pagano F, Schiavon S, Bordin A, Carrizzo A, Vecchione C, Valenti V, Chimenti I, de Falco E, Sciarretta S, Frati G (2017) A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxidative Med Cell Longev 2017:3920195–3920116. https://doi.org/10.1155/2017/3920195
Shao L, Zhang Y, Lan B, Wang J, Zhang Z, Zhang L, Xiao P, Meng Q, Geng YJ, Yu XY, Li Y (2017) MiRNA-sequence indicates that mesenchymal stem cells and Exosomes have similar mechanism to enhance cardiac repair. Biomed Res Int 2017:4150705–4150709. https://doi.org/10.1155/2017/4150705
Singla DK (2016) Stem cells and exosomes in cardiac repair. Curr Opin Pharmacol 27:19–23. https://doi.org/10.1016/j.coph.2016.01.003
Swynghedauw B (1999) Molecular mechanisms of myocardial remodeling. Physiol Rev 79(1):215–262. https://doi.org/10.1152/physrev.1999.79.1.215
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(6):2415–2424. https://doi.org/10.1159/000438594
Tokita Y, Tang XL, Li Q, Wysoczynski M, Hong KU, Nakamura S, Wu WJ, Xie W, Li D, Hunt G, Ou Q, Stowers H, Bolli R (2016) Repeated administrations of cardiac progenitor cells are markedly more effective than a single administration: a new paradigm in cell therapy. Circ Res 119(5):635–651. https://doi.org/10.1161/CIRCRESAHA.116.308937
van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, Hill JA, Olson EN (2008) Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci U S A 105(35):13027–13032. https://doi.org/10.1073/pnas.0805038105
Wang D, Zhai G, Ji Y, Jing H (2017) microRNA-10a targets T-box 5 to inhibit the development of cardiac hypertrophy. Int Heart J 58(1):100–106. https://doi.org/10.1536/ihj.16-020
Yu B, Zhang X, Li X (2014) Exosomes derived from mesenchymal stem cells. Int J Mol Sci 15(3):4142–4157. https://doi.org/10.3390/ijms15034142
Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, Gao L, Xie J, Xu B (2019) Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization. Cardiovasc Res 115(7):1205–1216. https://doi.org/10.1093/cvr/cvz040
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This work was supported by grants from the Natural Science Foundation of China (81470371), the Funds for Jiangsu Provincial Key Medical Discipline (ZDXKB2016013), the Funds for Jiangsu Provincial Medical Youth Talent (QNRC2016033 and Q201610), and the Programs of the Science Foundation in Nanjing (JQX15002 and 201605015).
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Editor: Tetsuji Okamoto
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Chen, F., Li, X., Zhao, J. et al. Bone marrow mesenchymal stem cell-derived exosomes attenuate cardiac hypertrophy and fibrosis in pressure overload induced remodeling. In Vitro Cell.Dev.Biol.-Animal 56, 567–576 (2020). https://doi.org/10.1007/s11626-020-00481-2
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DOI: https://doi.org/10.1007/s11626-020-00481-2