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[1]R. J. Simpson, S. S. Jensen and J. W. Lim: Proteomic profiling of exosomes: current perspectives. Proteomics, 8(19), 4083-99 (2008)
[2]S. Mathivanan and R. J. Simpson: ExoCarta: A compendium of exosomal proteins and RNA. Proteomics, 9(21), 4997-5000 (2009)
[3]J. A. Tickner, A. J. Urquhart, S. A. Stephenson, D. J. Richard and K. J. O’Byrne: Functions and therapeutic roles of exosomes in cancer. Front Oncol, 4, 127 (2014)
[4]J. De Toro, L. Herschlik, C. Waldner and C. Mongini: Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol, 6, 203 (2015)
[5]B. Zhang, Y. Yin, R. C. Lai and S. K. Lim: Immunotherapeutic potential of extracellular vesicles. Front Immunol, 5, 518 (2014)
[6]A. Kalani, A. Tyagi and N. Tyagi: Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol, 49(1), 590-600 (2014)
[7]S. Ailawadi, X. Wang, H. Gu and G. C. Fan: Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim Biophys Acta, 1852(1), 1-11 (2015)
[8]R. C. Lai, F. Arslan, M. M. Lee, N. S. Sze, A. Choo, T. S. Chen, M. Salto-Tellez, L. Timmers, C. N. Lee, R. M. El Oakley, G. Pasterkamp, D. P. de Kleijn and S. K. Lim: Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res, 4(3), 214-22 (2010)
[9]M. Khan, E. Nickoloff, T. Abramova, J. Johnson, S. K. Verma, P. Krishnamurthy, A. R. Mackie, E. Vaughan, V. N. Garikipati, C. Benedict, V. Ramirez, E. Lambers, A. Ito, E. Gao, S. Misener, T. Luongo, J. Elrod, G. Qin, S. R. Houser, W. J. Koch and R. Kishore: Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction. Circ Res, 117(1), 52-64 (2015)
[10]F. Arslan, R. C. Lai, M. B. Smeets, L. Akeroyd, A. Choo, E. N. Aguor, L. Timmers, H. V. van Rijen, P. A. Doevendans, G. Pasterkamp, S. K. Lim and D. P. de Kleijn: 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), 301-12 (2013)
[11]B. Yu, H. W. Kim, M. Gong, J. Wang, R. W. Millard, Y. Wang, M. Ashraf and M. Xu: Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol, 182, 349-60 (2015)
[12]Y. Wang, L. Zhang, Y. Li, L. Chen, X. Wang, W. Guo, X. Zhang, G. Qin, S. H. He, A. Zimmerman, Y. Liu, I. M. Kim, N. L. Weintraub and Y. Tang: Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol, 192, 61-9 (2015)
[13]L. Barile, V. Lionetti, E. Cervio, M. Matteucci, M. Gherghiceanu, L. M. Popescu, T. Torre, F. Siclari, T. Moccetti and G. Vassalli: Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res, 103(4), 530-41 (2014)
[14]S. Bian, L. Zhang, L. Duan, X. Wang, Y. Min and H. Yu: Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl), 92(4), 387-97 (2014)
[15]L. Chen, Y. Wang, Y. Pan, L. Zhang, C. Shen, G. Qin, M. Ashraf, N. Weintraub, G. Ma and Y. Tang: Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun, 431(3), 566-71 (2013)
[16]K. Kang, R. Ma, W. Cai, W. Huang, C. Paul, J. Liang, Y. Wang, T. Zhao, H. W. Kim, M. Xu, R. W. Millard and Z. Wen: Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction. Stem Cells Int, 2015, 659890 (2015)
[17]H. Xin, Y. Li, Y. Cui, J. J. Yang, Z. G. Zhang and M. Chopp: Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab, 33(11), 1711-5 (2013)
[18]I. Chimenti, E. Forte, F. Angelini, A. Giacomello and E. Messina: From ontogenesis to regeneration: learning how to instruct adult cardiac progenitor cells. Prog Mol Biol Transl Sci, 111, 109-37 (2012)
[19]M. R. Rosen, R. J. Myerburg, D. P. Francis, G. D. Cole and E. Marbán: Translating stem cell research to cardiac disease therapies: pitfalls and prospects for improvement. J Am Coll Cardiol, 64(9), 922-37 (2014)
[20]M. H. Yacoub and J. Terrovitis: CADUCEUS, SCIPIO, ALCADIA: Cell therapy trials using cardiac-derived cells for patients with post myocardial infarction LV dysfunction, still evolving. Glob Cardiol Sci Pract, 2013(1), 5-8 (2013)
[21]R. R. Makkar, R. R. Smith, K. Cheng, K. Malliaras, L. E. Thomson, D. Berman, L. S. Czer, L. Marbán, A. Mendizabal, P. V. Johnston, S. D. Russell, K. H. Schuleri, A. C. Lardo, G. Gerstenblith and E. Marbán: Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet, 379 (9819), 895-904 (2012)
[22]R. Bolli, A. R. Chugh, D. D’Amario, J. H. Loughran, M. F. Stoddard, S. Ikram, G. M. Beache, S. G. Wagner, A. Leri, T. Hosoda, F. Sanada, J. B. Elmore, P. Goichberg, D. Cappetta, N. K. Solankhi, I. Fahsah, D. G. Rokosh, M. S. Slaughter, J. Kajstura and P. Anversa: Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet, 378 (9806), 1847-57 (2011)
[23]J. Terrovitis, R. Lautamäki, M. Bonios, J. Fox, J. M. Engles, J. Yu, M. K. Leppo, M. G. Pomper, R. L. Wahl, J. Seidel, B. M. Tsui, F. M. Bengel, M. R. Abraham and E. Marbán: Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. J Am Coll Cardiol, 54(17), 1619-26 (2009)
[24]J. Terrovitis, K. F. Kwok, R. Lautamäki, J. M. Engles, A. S. Barth, E. Kizana, J. Miake, M. K. Leppo, J. Fox, J. Seidel, M. Pomper, R. L. Wahl, B. Tsui, F. Bengel, E. Marbán and M. R. Abraham: Ectopic expression of the sodium-iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single-photon emission computed tomography or positron emission tomography. J Am Coll Cardiol, 52(20), 1652-60 (2008)
[25]E. Forte, I. Chimenti, L. Barile, R. Gaetani, F. Angelini, V. Ionta, E. Messina and A. Giacomello: Cardiac cell therapy: the next (re)generation. Stem Cell Rev, 7(4), 1018-30 (2011)
[26]I. Chimenti, R. R. Smith, T. S. Li, G. Gerstenblith, E. Messina, A. Giacomello and E. Marbán: Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res, 106(5), 971-80 (2010)
[27]K. Malliaras, Y. Zhang, J. Seinfeld, G. Galang, E. Tseliou, K. Cheng, B. Sun, M. Aminzadeh and E. Marbán: Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med, 5(2), 191-209 (2013)
[28]M. Gnecchi, H. He, O. D. Liang, L. G. Melo, F. Morello, H. Mu, N. Noiseux, L. Zhang, R. E. Pratt, J. S. Ingwall and V. J. Dzau: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med, 11(4), 367-8 (2005)
[29]M. Gnecchi, Z. Zhang, A. Ni and V. J. Dzau: Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res, 103(11), 1204-19 (2008)
[30]L. Timmers, S. K. Lim, F. Arslan, J. S. Armstrong, I. E. Hoefer, P. A. Doevendans, J. J. Piek, R. M. El Oakley, A. Choo, C. N. Lee, G. Pasterkamp and D. P. de Kleijn: Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res, 1(2), 129-37 (2007)
[31]M. Gnecchi, H. He, N. Noiseux, O. D. Liang, L. Zhang, F. Morello, H. Mu, L. G. Melo, R. E. Pratt, J. S. Ingwall and V. J. Dzau: Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J, 20(6), 661-9 (2006)
[32]C. Siciliano, I. Chimenti, M. Ibrahim, C. Napoletano, G. Mangino, G. Scafetta, G. B. Zoccai, E. A. Rendina, A. Calogero, G. Frati and E. De Falco: Cardiosphere Conditioned Media Influence the Plasticity of Human Mediastinal Adipose Tissue-Derived Mesenchymal Stem Cells. Cell Transplant, 24(11), 2307-22 (2015)
[33]Y. Feng, W. Huang, W. Meng, A. G. Jegga, Y. Wang, W. Cai, H. W. Kim, Z. Pasha, Z. Wen, F. Rao, R. M. Modi, X. Yu and M. Ashraf: Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells, 32(2), 462-72 (2014)
[34]Y. Feng, W. Huang, M. Wani, X. Yu and M. Ashraf: Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One, 9(2), e88685 (2014)
[35]K. R. Vrijsen, J. P. Sluijter, M. W. Schuchardt, B. W. van Balkom, W. A. Noort, S. A. Chamuleau and P. A. Doevendans: Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells. J Cell Mol Med, 14(5), 1064-70 (2010)
[36]M. Stastna, I. Chimenti, E. Marbán and J. E. Van Eyk: Identification and functionality of proteomes secreted by rat cardiac stem cells and neonatal cardiomyocytes. Proteomics, 10(2), 245-53 (2010)
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Frontiers in Bioscience-Scholar (FBS) is published by IMR Press from Volume 13 Issue 1 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.
Exosomes isolation protocols: facts and artifacts for cardiac regeneration
1 Pasteur Institute - Cenci Bolognetti Foundation, “Sapienza” University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
2 Department of Molecular Medicine, “Sapienza” University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
3 Department of Medical Surgical Sciences and Biotechnology, “Sapienza” University of Rome, Corso della Repubblica 79, 04100 Latina, Italy
4 Department of Pediatric Cardiology, “Sapienza” University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
*Author to whom correspondence should be addressed.
Abstract
In recent years, exosomes have attracted increasing scientific interest and are no longer considered just as containers for cell waste, but as important mediators of intercellular communication. Among many biomedical research topics, a possible direct role of exosomes in the regenerative medicine field has been underlined in recent studies, including those regarding the so called “paracrine hypothesis”. In this perspective, a therapeutic role and/or use of exosomes for tissue regeneration seems to be plausible. However, the majority of the cells isolated and cultured in vitro are exposed to an exogenous exosomes source because of the wide use of foetal bovine serum as cell culture supplement. Bovine serum has been gradually considered as a major biological stimulus, but with still unknown outcome. In this review, we present the state of the art about the role of exosomes in regenerative medicine, particularly for the cardiovascular system. We also analyse the most commonly used exosome isolation techniques that, since their discovery, have undergone continuous development to reach the highest degree of scalability for future clinical translation.
Keywords
- Review
- Exosomes
- Isolation
- Stem Cells
- Cardiac Regeneration
- Review
References
- [1] R. J. Simpson, S. S. Jensen and J. W. Lim: Proteomic profiling of exosomes: current perspectives. Proteomics, 8(19), 4083-99 (2008)
- [2] S. Mathivanan and R. J. Simpson: ExoCarta: A compendium of exosomal proteins and RNA. Proteomics, 9(21), 4997-5000 (2009)
- [3] J. A. Tickner, A. J. Urquhart, S. A. Stephenson, D. J. Richard and K. J. O’Byrne: Functions and therapeutic roles of exosomes in cancer. Front Oncol, 4, 127 (2014)
- [4] J. De Toro, L. Herschlik, C. Waldner and C. Mongini: Emerging roles of exosomes in normal and pathological conditions: new insights for diagnosis and therapeutic applications. Front Immunol, 6, 203 (2015)
- [5] B. Zhang, Y. Yin, R. C. Lai and S. K. Lim: Immunotherapeutic potential of extracellular vesicles. Front Immunol, 5, 518 (2014)
- [6] A. Kalani, A. Tyagi and N. Tyagi: Exosomes: mediators of neurodegeneration, neuroprotection and therapeutics. Mol Neurobiol, 49(1), 590-600 (2014)
- [7] S. Ailawadi, X. Wang, H. Gu and G. C. Fan: Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim Biophys Acta, 1852(1), 1-11 (2015)
- [8] R. C. Lai, F. Arslan, M. M. Lee, N. S. Sze, A. Choo, T. S. Chen, M. Salto-Tellez, L. Timmers, C. N. Lee, R. M. El Oakley, G. Pasterkamp, D. P. de Kleijn and S. K. Lim: Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res, 4(3), 214-22 (2010)
- [9] M. Khan, E. Nickoloff, T. Abramova, J. Johnson, S. K. Verma, P. Krishnamurthy, A. R. Mackie, E. Vaughan, V. N. Garikipati, C. Benedict, V. Ramirez, E. Lambers, A. Ito, E. Gao, S. Misener, T. Luongo, J. Elrod, G. Qin, S. R. Houser, W. J. Koch and R. Kishore: Embryonic Stem Cell-Derived Exosomes Promote Endogenous Repair Mechanisms and Enhance Cardiac Function Following Myocardial Infarction. Circ Res, 117(1), 52-64 (2015)
- [10] F. Arslan, R. C. Lai, M. B. Smeets, L. Akeroyd, A. Choo, E. N. Aguor, L. Timmers, H. V. van Rijen, P. A. Doevendans, G. Pasterkamp, S. K. Lim and D. P. de Kleijn: 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), 301-12 (2013)
- [11] B. Yu, H. W. Kim, M. Gong, J. Wang, R. W. Millard, Y. Wang, M. Ashraf and M. Xu: Exosomes secreted from GATA-4 overexpressing mesenchymal stem cells serve as a reservoir of anti-apoptotic microRNAs for cardioprotection. Int J Cardiol, 182, 349-60 (2015)
- [12] Y. Wang, L. Zhang, Y. Li, L. Chen, X. Wang, W. Guo, X. Zhang, G. Qin, S. H. He, A. Zimmerman, Y. Liu, I. M. Kim, N. L. Weintraub and Y. Tang: Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol, 192, 61-9 (2015)
- [13] L. Barile, V. Lionetti, E. Cervio, M. Matteucci, M. Gherghiceanu, L. M. Popescu, T. Torre, F. Siclari, T. Moccetti and G. Vassalli: Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res, 103(4), 530-41 (2014)
- [14] S. Bian, L. Zhang, L. Duan, X. Wang, Y. Min and H. Yu: Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. J Mol Med (Berl), 92(4), 387-97 (2014)
- [15] L. Chen, Y. Wang, Y. Pan, L. Zhang, C. Shen, G. Qin, M. Ashraf, N. Weintraub, G. Ma and Y. Tang: Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun, 431(3), 566-71 (2013)
- [16] K. Kang, R. Ma, W. Cai, W. Huang, C. Paul, J. Liang, Y. Wang, T. Zhao, H. W. Kim, M. Xu, R. W. Millard and Z. Wen: Exosomes Secreted from CXCR4 Overexpressing Mesenchymal Stem Cells Promote Cardioprotection via Akt Signaling Pathway following Myocardial Infarction. Stem Cells Int, 2015, 659890 (2015)
- [17] H. Xin, Y. Li, Y. Cui, J. J. Yang, Z. G. Zhang and M. Chopp: Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab, 33(11), 1711-5 (2013)
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- [19] M. R. Rosen, R. J. Myerburg, D. P. Francis, G. D. Cole and E. Marbán: Translating stem cell research to cardiac disease therapies: pitfalls and prospects for improvement. J Am Coll Cardiol, 64(9), 922-37 (2014)
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- [22] R. Bolli, A. R. Chugh, D. D’Amario, J. H. Loughran, M. F. Stoddard, S. Ikram, G. M. Beache, S. G. Wagner, A. Leri, T. Hosoda, F. Sanada, J. B. Elmore, P. Goichberg, D. Cappetta, N. K. Solankhi, I. Fahsah, D. G. Rokosh, M. S. Slaughter, J. Kajstura and P. Anversa: Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet, 378 (9806), 1847-57 (2011)
- [23] J. Terrovitis, R. Lautamäki, M. Bonios, J. Fox, J. M. Engles, J. Yu, M. K. Leppo, M. G. Pomper, R. L. Wahl, J. Seidel, B. M. Tsui, F. M. Bengel, M. R. Abraham and E. Marbán: Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery. J Am Coll Cardiol, 54(17), 1619-26 (2009)
- [24] J. Terrovitis, K. F. Kwok, R. Lautamäki, J. M. Engles, A. S. Barth, E. Kizana, J. Miake, M. K. Leppo, J. Fox, J. Seidel, M. Pomper, R. L. Wahl, B. Tsui, F. Bengel, E. Marbán and M. R. Abraham: Ectopic expression of the sodium-iodide symporter enables imaging of transplanted cardiac stem cells in vivo by single-photon emission computed tomography or positron emission tomography. J Am Coll Cardiol, 52(20), 1652-60 (2008)
- [25] E. Forte, I. Chimenti, L. Barile, R. Gaetani, F. Angelini, V. Ionta, E. Messina and A. Giacomello: Cardiac cell therapy: the next (re)generation. Stem Cell Rev, 7(4), 1018-30 (2011)
- [26] I. Chimenti, R. R. Smith, T. S. Li, G. Gerstenblith, E. Messina, A. Giacomello and E. Marbán: Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res, 106(5), 971-80 (2010)
- [27] K. Malliaras, Y. Zhang, J. Seinfeld, G. Galang, E. Tseliou, K. Cheng, B. Sun, M. Aminzadeh and E. Marbán: Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med, 5(2), 191-209 (2013)
- [28] M. Gnecchi, H. He, O. D. Liang, L. G. Melo, F. Morello, H. Mu, N. Noiseux, L. Zhang, R. E. Pratt, J. S. Ingwall and V. J. Dzau: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med, 11(4), 367-8 (2005)
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- [31] M. Gnecchi, H. He, N. Noiseux, O. D. Liang, L. Zhang, F. Morello, H. Mu, L. G. Melo, R. E. Pratt, J. S. Ingwall and V. J. Dzau: Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J, 20(6), 661-9 (2006)
- [32] C. Siciliano, I. Chimenti, M. Ibrahim, C. Napoletano, G. Mangino, G. Scafetta, G. B. Zoccai, E. A. Rendina, A. Calogero, G. Frati and E. De Falco: Cardiosphere Conditioned Media Influence the Plasticity of Human Mediastinal Adipose Tissue-Derived Mesenchymal Stem Cells. Cell Transplant, 24(11), 2307-22 (2015)
- [33] Y. Feng, W. Huang, W. Meng, A. G. Jegga, Y. Wang, W. Cai, H. W. Kim, Z. Pasha, Z. Wen, F. Rao, R. M. Modi, X. Yu and M. Ashraf: Heat shock improves Sca-1+ stem cell survival and directs ischemic cardiomyocytes toward a prosurvival phenotype via exosomal transfer: a critical role for HSF1/miR-34a/HSP70 pathway. Stem Cells, 32(2), 462-72 (2014)
- [34] Y. Feng, W. Huang, M. Wani, X. Yu and M. Ashraf: Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS One, 9(2), e88685 (2014)
- [35] K. R. Vrijsen, J. P. Sluijter, M. W. Schuchardt, B. W. van Balkom, W. A. Noort, S. A. Chamuleau and P. A. Doevendans: Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells. J Cell Mol Med, 14(5), 1064-70 (2010)
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