Skip to main content

Advertisement

Log in

The Biological Mechanisms of Action of Cardiac Progenitor Cell Therapy

  • Myocardial Disease (A Abbate, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Cell therapy for cardiovascular diseases is regarded as a rapidly growing field within regenerative medicine. Different cellular populations enriched for cardiac progenitor cells (CPCs), or derivate a-cellular products, are currently under preclinical and clinical evaluation. Here, we have reviewed the described mechanisms whereby resident post-natal CPCs, isolated in different ways, act as a therapeutic product on the damaged myocardium.

Recent Findings

Several biological mechanisms of action have been described which can explain the multiple therapeutic effects of CPC treatment observed on cardiac function and remodelling. These mechanisms span from direct cardiovascular differentiation, through induction of resident progenitor proliferation, to paracrine effects on cardiac and non-cardiac cells mediated by exosomes and non-coding RNAs.

Summary

All the reported mechanisms of action support an integrated view including cardiomyogenesis, cardioprotection, and anti-fibrotic effects. Moreover, future developments of CPC therapy approaches may support cell-free strategies, exploiting effective pleiotropic cell-derived products, such as exosomes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016;37(42):3232–45. https://doi.org/10.1093/eurheartj/ehw334.

    Article  PubMed  Google Scholar 

  2. Schirone L, Forte M, Palmerio S, Yee D, Nocella C, Angelini F, et al. A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxid Med Cell Longev. 2017;2017:3920195. https://doi.org/10.1155/2017/3920195.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sanganalmath SK, Bolli R. Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res. 2013;113(6):810–34. https://doi.org/10.1161/CIRCRESAHA.113.300219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Menasche P. Cell therapy trials for heart regeneration—lessons learned and future directions. Nat Rev Cardiol. 2018; https://doi.org/10.1038/s41569-018-0013-0.

    Article  Google Scholar 

  5. van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature. 2014;509(7500):337–41. https://doi.org/10.1038/nature13309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hsieh PC, Segers VF, Davis ME, MacGillivray C, Gannon J, Molkentin JD, et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007;13(8):970–4. https://doi.org/10.1038/nm1618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, et al. Human cardiac stem cells. Proc Natl Acad Sci U S A. 2007;104(35):14068–73. https://doi.org/10.1073/pnas.0706760104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res. 2004;95(9):911–21. https://doi.org/10.1161/01.RES.0000147315.71699.51.

    Article  CAS  PubMed  Google Scholar 

  9. Smits AM, van Vliet P, Metz CH, Korfage T, Sluijter JP, Doevendans PA, et al. Human cardiomyocyte progenitor cells differentiate into functional mature cardiomyocytes: an in vitro model for studying human cardiac physiology and pathophysiology. Nat Protoc. 2009;4(2):232–43. https://doi.org/10.1038/nprot.2008.229.

    Article  CAS  PubMed  Google Scholar 

  10. Barile L, Chimenti I, Gaetani R, Forte E, Miraldi F, Frati G, et al. Cardiac stem cells: isolation, expansion and experimental use for myocardial regeneration. Nat Clin Pract Cardiovasc Med. 2007;4(Suppl 1):S9–S14. https://doi.org/10.1038/ncpcardio0738.

    Article  CAS  PubMed  Google Scholar 

  11. Gaetani R, Feyen DA, Doevendans PA, Gremmels H, Forte E, Fledderus JO, et al. Different types of cultured human adult cardiac progenitor cells have a high degree of transcriptome similarity. J Cell Mol Med. 2014;18(11):2147–51. https://doi.org/10.1111/jcmm.12458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. • Zwetsloot PP, Vegh AM, Jansen OF, Lorkeers SJ, van Hout GP, Currie GL, et al. Cardiac stem cell treatment in myocardial infarction: a systematic review and meta-analysis of preclinical studies. Circ Res. 2016;118(8):1223–32. https://doi.org/10.1161/CIRCRESAHA.115.307676. This study provides a comprehensive metanalysis of alla available pre-clinical translational data for cardiac cell therapy.

    Article  CAS  PubMed  Google Scholar 

  13. Makkar RR, Smith RR, Cheng K, Malliaras K, Thomson LE, Berman D, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet. 2012;379(9819):895–904. https://doi.org/10.1016/S0140-6736(12)60195-0.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lee ST, White AJ, Matsushita S, Malliaras K, Steenbergen C, Zhang Y, et al. Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. J Am Coll Cardiol. 2011;57(4):455–65. https://doi.org/10.1016/j.jacc.2010.07.049.

    Article  PubMed  Google Scholar 

  15. Bolli R, Chugh AR, D'Amario D, Loughran JH, Stoddard MF, Ikram S, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. Lancet. 2011;378(9806):1847–57. https://doi.org/10.1016/S0140-6736(11)61590-0.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yacoub MH, Terrovitis J, 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;2013(1):5–8. https://doi.org/10.5339/gcsp.2013.3.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Peruzzi M, De Falco E, Abbate A, Biondi-Zoccai G, Chimenti I, Lotrionte M, et al. State of the art on the evidence base in cardiac regenerative therapy: overview of 41 systematic reviews. Biomed Res Int. 2015;2015:613782. https://doi.org/10.1155/2015/613782.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Emmert MY. Cell-based cardiac regeneration. Eur Heart J. 2017;38(15):1095–8. https://doi.org/10.1093/eurheartj/ehx152.

    Article  PubMed  Google Scholar 

  19. Forte E, Chimenti I, Barile L, Gaetani R, Angelini F, Ionta V, et al. Cardiac cell therapy: the next (re)generation. Stem Cell Rev. 2011;7(4):1018–30. https://doi.org/10.1007/s12015-011-9252-8.

    Article  PubMed  Google Scholar 

  20. Li TS, Cheng K, Malliaras K, Smith RR, Zhang Y, Sun B, et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J Am Coll Cardiol. 2012;59(10):942–53. https://doi.org/10.1016/j.jacc.2011.11.029.

    Article  PubMed  PubMed Central  Google Scholar 

  21. • Kanazawa H, Tseliou E, Malliaras K, Yee K, Dawkins JF, De Couto G, et al. Cellular postconditioning: allogeneic cardiosphere-derived cells reduce infarct size and attenuate microvascular obstruction when administered after reperfusion in pigs with acute myocardial infarction. Circ Heart Fail. 2015;8(2):322–32. https://doi.org/10.1161/CIRCHEARTFAILURE.114.001484. This study proposes a novel protective mechanism early after ischemic reperfusion.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114(6):763–76.

    Article  CAS  PubMed  Google Scholar 

  23. Hatzistergos KE, Saur D, Seidler B, Balkan W, Breton M, Valasaki K, et al. Stimulatory effects of mesenchymal stem cells on cKit+ cardiac stem cells are mediated by SDF1/CXCR4 and SCF/cKit signaling pathways. Circ Res. 2016;119(8):921–30. https://doi.org/10.1161/CIRCRESAHA.116.309281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dawn B, Stein AB, Urbanek K, Rota M, Whang B, Rastaldo R, et al. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci U S A. 2005;102(10):3766–71. https://doi.org/10.1073/pnas.0405957102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jesty SA, Steffey MA, Lee FK, Breitbach M, Hesse M, Reining S, et al. c-kit+ precursors support postinfarction myogenesis in the neonatal, but not adult, heart. Proc Natl Acad Sci U S A. 2012;109(33):13380–5. https://doi.org/10.1073/pnas.1208114109.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A. 2003;100(21):12313–8. https://doi.org/10.1073/pnas.2132126100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. van Vliet P, Roccio M, Smits AM, van Oorschot AA, Metz CH, van Veen TA, et al. Progenitor cells isolated from the human heart: a potential cell source for regenerative therapy. Neth Heart J. 2008;16(5):163–9.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Matsuura K, Nagai T, Nishigaki N, Oyama T, Nishi J, Wada H, et al. Adult cardiac Sca-1-positive cells differentiate into beating cardiomyocytes. J Biol Chem. 2004;279(12):11384–91. https://doi.org/10.1074/jbc.M310822200.

    Article  CAS  PubMed  Google Scholar 

  29. Goumans MJ, de Boer TP, Smits AM, van Laake LW, van Vliet P, Metz CH, et al. TGF-beta1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res. 2007;1(2):138–49. https://doi.org/10.1016/j.scr.2008.02.003.

    Article  CAS  PubMed  Google Scholar 

  30. Mohri T, Fujio Y, Maeda M, Ito T, Iwakura T, Oshima Y, et al. Leukemia inhibitory factor induces endothelial differentiation in cardiac stem cells. J Biol Chem. 2006;281(10):6442–7. https://doi.org/10.1074/jbc.M508969200.

    Article  CAS  PubMed  Google Scholar 

  31. Iwakura T, Mohri T, Hamatani T, Obana M, Yamashita T, Maeda M, et al. STAT3/Pim-1 signaling pathway plays a crucial role in endothelial differentiation of cardiac resident Sca-1+ cells both in vitro and in vivo. J Mol Cell Cardiol. 2011;51(2):207–14. https://doi.org/10.1016/j.yjmcc.2011.04.013.

    Article  CAS  PubMed  Google Scholar 

  32. Chimenti I, Gaetani R, Barile L, Forte E, Ionta V, Angelini F, et al. Isolation and expansion of adult cardiac stem/progenitor cells in the form of cardiospheres from human cardiac biopsies and murine hearts. Methods Mol Biol. 2012;879:327–38. https://doi.org/10.1007/978-1-61779-815-3_19.

    Article  CAS  PubMed  Google Scholar 

  33. Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115(7):896–908. https://doi.org/10.1161/CIRCULATIONAHA.106.655209.

    Article  CAS  PubMed  Google Scholar 

  34. Davis DR, Ruckdeschel Smith R, Marbán E. Human cardiospheres are a source of stem cells with cardiomyogenic potential. Stem Cells. 2010;28(5):903–4. https://doi.org/10.1002/stem.413.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103(11):1204–19. https://doi.org/10.1161/CIRCRESAHA.108.176826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chimenti I, Smith RR, Li TS, Gerstenblith G, Messina E, Giacomello A, et al. Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice. Circ Res. 2010;106(5):971–80. https://doi.org/10.1161/CIRCRESAHA.109.210682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Stastna M, Chimenti I, Marban E, Van Eyk JE. Identification and functionality of proteomes secreted by rat cardiac stem cells and neonatal cardiomyocytes. Proteomics. 2010;10(2):245–53. https://doi.org/10.1002/pmic.200900515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cheng K, Malliaras K, Smith RR, Shen D, Sun B, Blusztajn A, et al. Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair. JACC Heart Fail. 2014;2(1):49–61. https://doi.org/10.1016/j.jchf.2013.08.008.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Siciliano C, Chimenti I, Ibrahim M, Napoletano C, Mangino G, Scafetta G, et al. Cardiosphere conditioned media influence the plasticity of human mediastinal adipose tissue-derived mesenchymal stem cells. Cell Transplant. 2015;24(11):2307–22. https://doi.org/10.3727/096368914X685771.

    Article  PubMed  Google Scholar 

  40. Miyamoto S, Kawaguchi N, Ellison GM, Matsuoka R, Shin'oka T, Kurosawa H. Characterization of long-term cultured c-kit+ cardiac stem cells derived from adult rat hearts. Stem Cells Dev. 2010;19(1):105–16. https://doi.org/10.1089/scd.2009.0041.

    Article  CAS  PubMed  Google Scholar 

  41. Huang C, Gu H, Yu Q, Manukyan MC, Poynter JA, Wang M. Sca-1+ cardiac stem cells mediate acute cardioprotection via paracrine factor SDF-1 following myocardial ischemia/reperfusion. PLoS One. 2011;6(12):e29246. https://doi.org/10.1371/journal.pone.0029246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jackson R, Tilokee EL, Latham N, Mount S, Rafatian G, Strydhorst J, et al. Paracrine engineering of human cardiac stem cells with insulin-like growth factor 1 enhances myocardial repair. J Am Heart Assoc. 2015;4(9):e002104. https://doi.org/10.1161/JAHA.115.002104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tilokee EL, Latham N, Jackson R, Mayfield AE, Ye B, Mount S, et al. Paracrine engineering of human explant-derived cardiac stem cells to over-express stromal-cell derived factor 1α enhances myocardial repair. Stem Cells. 2016;34(7):1826–35. https://doi.org/10.1002/stem.2373.

    Article  CAS  PubMed  Google Scholar 

  44. Mayfield AE, Kanda P, Nantsios A, Parent S, Mount S, Dixit S, et al. Interleukin-6 mediates post-infarct repair by cardiac explant-derived stem cells. Theranostics. 2017;7(19):4850–61. https://doi.org/10.7150/thno.19435.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Toran JL, Aguilar S, Lopez JA, Torroja C, Quintana JA, Santiago C, et al. CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome. Sci Rep. 2017;7(1):12490. https://doi.org/10.1038/s41598-017-11976-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. • Tang J, Shen D, Caranasos TG, Wang Z, Vandergriff AC, Allen TA, et al. Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome. Nat Commun. 2017;8:13724. https://doi.org/10.1038/ncomms13724. This study introduces a novel biotechnological approach to deliver CPC-conditioned media.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mayfield AE, Fitzpatrick ME, Latham N, Tilokee EL, Villanueva M, Mount S, et al. The impact of patient co-morbidities on the regenerative capacity of cardiac explant-derived stem cells. Stem Cell Res Ther. 2016;7(1):60. https://doi.org/10.1186/s13287-016-0321-4.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Malliaras K, Ibrahim A, Tseliou E, Liu W, Sun B, Middleton RC, et al. Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. EMBO Mol Med. 2014;6(6):760–77. https://doi.org/10.1002/emmm.201303626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, et al. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med. 2013;5(2):191–209. https://doi.org/10.1002/emmm.201201737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xie Y, Ibrahim A, Cheng K, Wu Z, Liang W, Malliaras K, et al. Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. Stem Cells. 2014;32(9):2397–406. https://doi.org/10.1002/stem.1736.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Tang XL, Rokosh G, Sanganalmath SK, Yuan F, Sato H, Mu J, et al. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation. 2010;121(2):293–305. https://doi.org/10.1161/CIRCULATIONAHA.109.871905.

    Article  PubMed  PubMed Central  Google Scholar 

  52. D'Amario D, Leone AM, Iaconelli A, Luciani N, Gaudino M, Kannappan R, et al. Growth properties of cardiac stem cells are a novel biomarker of patients’ outcome after coronary bypass surgery. Circulation. 2014;129(2):157–72. https://doi.org/10.1161/CIRCULATIONAHA.113.006591.

    Article  CAS  PubMed  Google Scholar 

  53. Cambria E, Pasqualini FS, Wolint P, Günter J, Steiger J, Bopp A, et al. Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types. NPJ Regen Med. 2017;2:17. https://doi.org/10.1038/s41536-017-0024-1.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ibrahim AG, Cheng K, Marbán E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports. 2014;2(5):606–19. https://doi.org/10.1016/j.stemcr.2014.04.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gallet R, Dawkins J, Valle J, Simsolo E, de Couto G, Middleton R, et al. Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. Eur Heart J. 2017;38(3):201–11. https://doi.org/10.1093/eurheartj/ehw240.

    Article  PubMed  Google Scholar 

  56. Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. 2006;Chapter 3:Unit 3.22. doi:https://doi.org/10.1002/0471143030.cb0322s30.

    Article  Google Scholar 

  57. Conigliaro A, Fontana S, Raimondo S, Alessandro R. Exosomes: nanocarriers of biological messages. Adv Exp Med Biol. 2017;998:23–43. https://doi.org/10.1007/978-981-10-4397-0_2.

    Article  PubMed  Google Scholar 

  58. Urbanelli L, Magini A, Buratta S, Brozzi A, Sagini K, Polchi A, et al. Signaling pathways in exosomes biogenesis, secretion and fate. Genes (Basel). 2013;4(2):152–70. https://doi.org/10.3390/genes4020152.

    Article  CAS  Google Scholar 

  59. Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine mechanisms of mesenchymal stem cells in tissue repair. Methods Mol Biol. 2016;1416:123–46. https://doi.org/10.1007/978-1-4939-3584-0_7.

    Article  CAS  PubMed  Google Scholar 

  60. Glembotski CC. Expanding the paracrine hypothesis of stem cell-mediated repair in the heart: when the unconventional becomes conventional. Circ Res. 2017;120(5):772–4. https://doi.org/10.1161/CIRCRESAHA.116.310298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Jing H, He X, Zheng J. Exosomes and regenerative medicine: state of the art and perspectives. Transl Res. 2018;196:1–16. https://doi.org/10.1016/j.trsl.2018.01.005.

    Article  CAS  PubMed  Google Scholar 

  62. Bjørge IM, Kim SY, Mano JF, Kalionis B, Chrzanowski W. Extracellular vesicles, exosomes and shedding vesicles in regenerative medicine—a new paradigm for tissue repair. Biomater Sci. 2017;6(1):60–78. https://doi.org/10.1039/c7bm00479f.

    Article  CAS  PubMed  Google Scholar 

  63. Angelini F, Ionta V, Rossi F, Pagano F, Chimenti I, Messina E, et al. Exosomes isolation protocols: facts and artifacts for cardiac regeneration. Front Biosci (Schol Ed). 2016;8:303–11.

    Article  Google Scholar 

  64. Barile L, Lionetti V, Cervio E, Matteucci M, Gherghiceanu M, Popescu LM, et al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res. 2014;103(4):530–41. https://doi.org/10.1093/cvr/cvu167.

    Article  CAS  PubMed  Google Scholar 

  65. Chen L, Wang Y, Pan Y, Zhang L, Shen C, Qin G, et al. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun. 2013;431(3):566–71. https://doi.org/10.1016/j.bbrc.2013.01.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Li S, Jiang J, Yang Z, Li Z, Ma X, Li X. Cardiac progenitor cellderived exosomes promote H9C2 cell growth via Akt/mTOR activation. Int J Mol Med. 2018; https://doi.org/10.3892/ijmm.2018.3699.

  67. • Barile L, Cervio E, Lionetti V, Milano G, Ciullo A, Biemmi V, et al. Cardioprotection by cardiac progenitor cell-secreted exosomes: role of pregnancy-associated plasma protein-A. Cardiovasc Res. 2018;114(7):992–1005. https://doi.org/10.1093/cvr/cvy055. This study investigates the whole protein content of CPC exosomes by proteomic analysis.

    Article  PubMed  Google Scholar 

  68. D'Elia P, Ionta V, Chimenti I, Angelini F, Miraldi F, Pala A, et al. Analysis of pregnancy-associated plasma protein A production in human adult cardiac progenitor cells. Biomed Res Int. 2013;2013:190178. https://doi.org/10.1155/2013/190178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Vrijsen KR, Maring JA, Chamuleau SA, Verhage V, Mol EA, Deddens JC, et al. Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv Healthc Mater. 2016;5(19):2555–65. https://doi.org/10.1002/adhm.201600308.

    Article  CAS  PubMed  Google Scholar 

  70. Lang JK, Young RF, Ashraf H, Canty JM Jr. Inhibiting extracellular vesicle release from human cardiosphere derived cells with lentiviral knockdown of nSMase2 differentially effects proliferation and apoptosis in cardiomyocytes, fibroblasts and endothelial cells in vitro. PLoS One. 2016;11(11):e0165926. https://doi.org/10.1371/journal.pone.0165926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vandergriff AC, de Andrade JB, Tang J, Hensley MT, Piedrahita JA, Caranasos TG, et al. Intravenous cardiac stem cell-derived exosomes ameliorate cardiac dysfunction in doxorubicin induced dilated cardiomyopathy. Stem Cells Int. 2015;2015:960926. https://doi.org/10.1155/2015/960926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cambier L, Giani JF, Liu W, Ijichi T, Echavez AK, Valle J, et al. Angiotensin II-induced end-organ damage in mice is attenuated by human exosomes and by an exosomal Y RNA fragment. Hypertension. 2018; https://doi.org/10.1161/HYPERTENSIONAHA.118.11239.

    Article  CAS  PubMed  Google Scholar 

  73. Aminzadeh MA, Rogers RG, Fournier M, Tobin RE, Guan X, Childers MK, et al. Exosome-mediated benefits of cell therapy in mouse and human models of duchenne muscular dystrophy. Stem Cell Reports. 2018;10(3):942–55. https://doi.org/10.1016/j.stemcr.2018.01.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Feng J, Li Y, Nie Y. Non-cardiomyocytes in Heart Regeneration. Curr Drug Targets. 2018; https://doi.org/10.2174/1389450119666180518111931.

    Article  CAS  PubMed  Google Scholar 

  75. Eschenhagen T. A new concept of fibroblast dynamics in post-myocardial infarction remodeling. J Clin Invest. 2018;128(5):1731–3. https://doi.org/10.1172/JCI121079.

    Article  PubMed  Google Scholar 

  76. Tseliou E, Fouad J, Reich H, Slipczuk L, de Couto G, Aminzadeh M, et al. Fibroblasts rendered antifibrotic, antiapoptotic, and angiogenic by priming with cardiosphere-derived extracellular membrane vesicles. J Am Coll Cardiol. 2015;66(6):599–611. https://doi.org/10.1016/j.jacc.2015.05.068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tseliou E, Reich H, de Couto G, Terrovitis J, Sun B, Liu W, et al. Cardiospheres reverse adverse remodeling in chronic rat myocardial infarction: roles of soluble endoglin and Tgf-beta signaling. Basic Res Cardiol. 2014;109(6):443. https://doi.org/10.1007/s00395-014-0443-8.

    Article  CAS  PubMed  Google Scholar 

  78. Cheng K, Ibrahim A, Hensley MT, Shen D, Sun B, Middleton R, et al. Relative roles of CD90 and c-kit to the regenerative efficacy of cardiosphere-derived cells in humans and in a mouse model of myocardial infarction. J Am Heart Assoc. 2014;3(5):e001260. https://doi.org/10.1161/JAHA.114.001260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gago-Lopez N, Awaji O, Zhang Y, Ko C, Nsair A, Liem D, et al. THY-1 receptor expression differentiates cardiosphere-derived cells with divergent cardiogenic differentiation potential. Stem Cell Reports. 2014;2(5):576–91. https://doi.org/10.1016/j.stemcr.2014.03.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Castaldo C, Chimenti I. Cardiac progenitor cells: the matrix has you. Stem Cells Transl Med. 2018; https://doi.org/10.1002/sctm.18-0023.

    Article  PubMed Central  Google Scholar 

  81. Courties G, Heidt T, Sebas M, Iwamoto Y, Jeon D, Truelove J, et al. In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. J Am Coll Cardiol. 2014;63(15):1556–66. https://doi.org/10.1016/j.jacc.2013.11.023.

    Article  CAS  PubMed  Google Scholar 

  82. Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018; https://doi.org/10.1002/jcp.26429.

    Article  CAS  PubMed  Google Scholar 

  83. •• de Couto G, Liu W, Tseliou E, Sun B, Makkar N, Kanazawa H, et al. Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. J Clin Invest, This study provides novel exciting insights on macrophage polarization as a mechanism of cardioprotection after I/R injury. 2015;125(8):3147–62. https://doi.org/10.1172/JCI81321.

    Article  PubMed  Google Scholar 

  84. Cambier L, de Couto G, Ibrahim A, Echavez AK, Valle J, Liu W, et al. Y RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion. EMBO Mol Med. 2017;9(3):337–52. https://doi.org/10.15252/emmm.201606924.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. de Couto G, Gallet R, Cambier L, Jaghatspanyan E, Makkar N, Dawkins JF, et al. Exosomal microRNA transfer into macrophages mediates cellular postconditioning. Circulation. 2017;136(2):200–14. https://doi.org/10.1161/CIRCULATIONAHA.116.024590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chimenti I, Frati G. Cell-derived exosomes for cardiovascular therapies: Y (Not) RNAs? Hypertension. 2018; https://doi.org/10.1161/HYPERTENSIONAHA.118.10684.

    Article  CAS  PubMed  Google Scholar 

  87. Sluijter JPGa. Exosomal microRNA clusters are important for the therapeutic effect of cardiac progenitor cells. Circulation Research. 2015;116(2):219--221. doi:https://doi.org/10.1161/CIRCRESAHA.114.305673.

    Article  CAS  PubMed  Google Scholar 

  88. Gray WD, French KM, Ghosh-Choudhary S, Maxwell JT, Brown ME, Platt MO, et al. Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circulation Research. 2015;116(2):255–63. https://doi.org/10.1161/CIRCRESAHA.116.304360.

    Article  CAS  PubMed  Google Scholar 

  89. Cavarretta E, Frati G. MicroRNAs in coronary heart disease: ready to enter the clinical arena? Biomed Res Int. 2016;2016:2150763. https://doi.org/10.1155/2016/2150763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Condorelli G, Latronico MV, Cavarretta E. microRNAs in cardiovascular diseases: current knowledge and the road ahead. J Am Coll Cardiol. 2014;63(21):2177–87. https://doi.org/10.1016/j.jacc.2014.01.050.

    Article  CAS  PubMed  Google Scholar 

  91. Prathipati PNSSMPK. Stem cell-derived exosomes, autophagy, extracellular matrix turnover, and miRNAs in cardiac regeneration during stem cell therapy. Stem Cell Reviews and Reports. 2017;13(1):79–91. https://doi.org/10.1007/s12015-016-9696-y.

    Article  CAS  PubMed  Google Scholar 

  92. Chen L, Wang Y, Pan Y, Zhang L, Shen C, Qin G, et al. Cardiac progenitor-derived Exosomes protect ischemic myocardium from acute ischemia/reperfusion injury. Biochem Biophys Res Commun. 2013;431(3):566–71. https://doi.org/10.1016/j.bbrc.2013.01.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell. 2008;133(2):217–22. https://doi.org/10.1016/j.cell.2008.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hu S, Huang M, Li Z, Jia F, Ghosh Z, Lijkwan MA, et al. MicroRNA-210 as a novel therapy for treatment of ischemic heart disease. Circulation. 2010;122(11 Suppl):S124–31. https://doi.org/10.1161/CIRCULATIONAHA.109.928424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chimenti I, Pagano F, Cavarretta E, Angelini F, Peruzzi M, Barretta A, et al. Beta-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells. Sci Rep. 2016;6:36774. https://doi.org/10.1038/srep36774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kowalski MP, Krude T. Functional roles of non-coding Y RNAs. Int J Biochem Cell Biol. 2015;66:20–9. https://doi.org/10.1016/j.biocel.2015.07.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Tosar JP, Gámbaro F, Sanguinetti J, Bonilla B, Witwer KW, Cayota A. Assessment of small RNA sorting into different extracellular fractions revealed by high-throughput sequencing of breast cell lines. Nucleic Acids Res. 2015;43(11):5601–16. https://doi.org/10.1093/nar/gkv432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. van Balkom BW, Eisele AS, Pegtel DM, Bervoets S, Verhaar MC. Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting. J Extracell Vesicles. 2015;4:26760.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

SS and IC are supported by a grant from the Italian Ministry of Health, protocol GR-2013-02355401. GF is supported by a grant from the Italian Ministry of Education, University and Research, protocol 20157ATSLF. EDF is supported by a grant from the Italian Ministry of Health, protocol CO-2013-02359690.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Isotta Chimenti.

Ethics declarations

Conflict of Interest

Francesca Pagano, Vittorio Picchio, Francesco Angelini, Alessandra Iaccarino, Mariangela Peruzzi, Elena Cavarretta, Giuseppe Biondi-Zoccai, Sebastiano Sciarretta, Elena De Falco, and Isotta Chimenti declare that they have no conflict of interest.

Giacomo Frati is inventor of patents WO2005012510, owned by “La Sapienza” University of Rome.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Myocardial Disease

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pagano, F., Picchio, V., Angelini, F. et al. The Biological Mechanisms of Action of Cardiac Progenitor Cell Therapy. Curr Cardiol Rep 20, 84 (2018). https://doi.org/10.1007/s11886-018-1031-6

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-018-1031-6

Keywords

Navigation