DOI QR코드

DOI QR Code

Characterization of human cardiac mesenchymal stromal cells and their extracellular vesicles comparing with human bone marrow derived mesenchymal stem cells

  • Kang, In Sook (The Graduate School, Yonsei University College of Medicine) ;
  • Suh, Joowon (Department of Life Sciences and College of Natural Sciences, Ewha Womans University) ;
  • Lee, Mi-Ni (Department of Life Sciences and College of Natural Sciences, Ewha Womans University) ;
  • Lee, Chaeyoung (Department of Life Sciences and College of Natural Sciences, Ewha Womans University) ;
  • Jin, Jing (Department of Life Sciences and College of Natural Sciences, Ewha Womans University) ;
  • Lee, Changjin (Rosetta Exosome Inc.) ;
  • Yang, Young Il (Paik Institute for Clinical Research, Inje University College of Medicine) ;
  • Jang, Yangsoo (The Graduate School, Yonsei University College of Medicine) ;
  • Oh, Goo Taeg (Department of Life Sciences and College of Natural Sciences, Ewha Womans University)
  • Received : 2019.09.27
  • Accepted : 2019.10.28
  • Published : 2020.02.29

Abstract

Cardiac regeneration with adult stem-cell (ASC) therapy is a promising field to address advanced cardiovascular diseases. In addition, extracellular vesicles (EVs) from ASCs have been implicated in acting as paracrine factors to improve cardiac functions in ASC therapy. In our work, we isolated human cardiac mesenchymal stromal cells (h-CMSCs) by means of three-dimensional organ culture (3D culture) during ex vivo expansion of cardiac tissue, to compare the functional efficacy with human bone-marrow derived mesenchymal stem cells (h-BM-MSCs), one of the actively studied ASCs. We characterized the h-CMSCs as CD90low, c-kitnegative, CD105positive phenotype and these cells express NANOG, SOX2, and GATA4. To identify the more effective type of EVs for angiogenesis among the different sources of ASCs, we isolated EVs which were derived from CMSCs with either normoxic or hypoxic condition and BM-MSCs. Our in vitro tube-formation results demonstrated that the angiogenic effects of EVs from hypoxia-treated CMSCs (CMSC-Hpx EVs) were greater than the well-known effects of EVs from BM-MSCs (BM-MSC EVs), and these were even comparable to human vascular endothelial growth factor (hVEGF), a potent angiogenic factor. Therefore, we present here that CD90lowc-kitnegativeCD105positive CMSCs under hypoxic conditions secrete functionally superior EVs for in vitro angiogenesis. Our findings will allow more insights on understanding myocardial repair.

Keywords

References

  1. Benjamin EJ, Muntner P, Alonso A et al (2019) Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation 139, e56-e528
  2. Cambria E, Pasqualini FS, Wolint P et al (2017) Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types. NPJ Regen Med 2, 17 https://doi.org/10.1038/s41536-017-0024-1
  3. Makkar RR, Smith RR, Cheng K et al (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895-904 https://doi.org/10.1016/S0140-6736(12)60195-0
  4. Parizadeh SM, Jafarzadeh-Esfehani R, Ghandehari M et al (2019) Stem cell therapy: A novel approach for myocardial infarction. J Cell Physiol 234, 16904-16912 https://doi.org/10.1002/jcp.28381
  5. Yun CW and Lee SH (2019) Enhancement of Functionality and Therapeutic Efficacy of Cell-Based Therapy Using Mesenchymal Stem Cells for Cardiovascular Disease. Int J Mol Sci 20, 982 https://doi.org/10.3390/ijms20040982
  6. Barile L, Messina E, Giacomello A and Marban E (2007) Endogenous cardiac stem cells. Prog Cardiovasc Dis 50, 31-48 https://doi.org/10.1016/j.pcad.2007.03.005
  7. Smith RR, Barile L, Cho HC et al (2007) Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115, 896-908 https://doi.org/10.1161/CIRCULATIONAHA.106.655209
  8. Beltrami AP, Barlucchi L, Torella D et al (2003) Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration. Cell 114, 763-776 https://doi.org/10.1016/S0092-8674(03)00687-1
  9. Cheng K, Ibrahim A, Hensley MT et al (2014) 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 3, e001260 https://doi.org/10.1161/JAHA.114.001260
  10. Gude NA and Sussman MA (2018) Chasing c-Kit through the heart: Taking a broader view. Pharmacol Res 127, 110-115 https://doi.org/10.1016/j.phrs.2017.06.007
  11. Gago-Lopez N, Awaji O, Zhang Y et al (2014) THY-1 receptor expression differentiates cardiosphere-derived cells with divergent cardiogenic differentiation potential. Stem Cell Reports 2, 576-591 https://doi.org/10.1016/j.stemcr.2014.03.003
  12. Shen D, Shen M, Liang H et al (2018) Therapeutic benefits of CD90-negative cardiac stromal cells in rats with a 30-day chronic infarct. J Cell Mol Med 22, 1984-1991 https://doi.org/10.1111/jcmm.13517
  13. Eschenhagen T, Bolli R, Braun T et al (2017) Cardiomyocyte Regeneration. Circulation 136, 680-686 https://doi.org/10.1161/CIRCULATIONAHA.117.029343
  14. Agarwal U, George A, Bhutani S et al (2017) Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell-Derived Exosomes From Pediatric Patients. Circ Res 120, 701-712 https://doi.org/10.1161/CIRCRESAHA.116.309935
  15. Bei Y, Das S, Rodosthenous RS et al (2017) Extracellular Vesicles in Cardiovascular Theranostics. Theranostics 7, 4168-4182 https://doi.org/10.7150/thno.21274
  16. Ibrahim A and Marban E (2016) Exosomes: Fundamental Biology and Roles in Cardiovascular Physiology. Annu Rev Physiol 78, 67-83 https://doi.org/10.1146/annurev-physiol-021115-104929
  17. Zamani P, Fereydouni N, Butler AE, Navashenaq JG and Sahebkar A (2018) The therapeutic and diagnostic role of exosomes in cardiovascular diseases. Trends Cardiovasc Med 29, 313-323
  18. Ibrahim Ahmed GE, Cheng K and Marban E (2014) Exosomes as Critical Agents of Cardiac Regeneration Triggered by Cell Therapy. Stem Cell Reports 2, 606-619 https://doi.org/10.1016/j.stemcr.2014.04.006
  19. Sahoo S and Losordo DW (2014) Exosomes and cardiac repair after myocardial infarction. Circ Res 114, 333-344 https://doi.org/10.1161/CIRCRESAHA.114.300639
  20. Xue C, Shen Y, Li X et al (2018) Exosomes Derived from Hypoxia-Treated Human Adipose Mesenchymal Stem Cells Enhance Angiogenesis Through the PKA Signaling Pathway. Stem Cells Dev 27, 456-465 https://doi.org/10.1089/scd.2017.0296
  21. Namazi H, Mohit E, Namazi I et al (2018) Exosomes secreted by hypoxic cardiosphere-derived cells enhance tube formation and increase pro-angiogenic miRNA. J Cell Biochem 119, 4150-4160 https://doi.org/10.1002/jcb.26621
  22. Li TS, Cheng K, Malliaras K et al (2012) 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 59, 942-953 https://doi.org/10.1016/j.jacc.2011.11.029
  23. Maleki M, Ghanbarvand F, Reza Behvarz M, Ejtemaei M and Ghadirkhomi E (2014) Comparison of mesenchymal stem cell markers in multiple human adult stem cells. Int J Stem Cells 7, 118-126 https://doi.org/10.15283/ijsc.2014.7.2.118
  24. Durocher D, Charron F, Warren R, Schwartz RJ and Nemer M (1997) The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors. EMBO J 16, 5687-5696 https://doi.org/10.1093/emboj/16.18.5687
  25. Kim JT, Chung HJ, Seo JY et al (2015) A fibrin-supported myocardial organ culture for isolation of cardiac stem cells via the recapitulation of cardiac homeostasis. Biomaterials 48, 66-83 https://doi.org/10.1016/j.biomaterials.2015.01.041
  26. van Berlo JH, Kanisicak O, Maillet M et al (2014) c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509, 337-341 https://doi.org/10.1038/nature13309
  27. G K Harvard calls for retraction of dozens of studies by noted cardiac researcher. https://www.nytimes.com/2018/10/15/health/piero-anversa-fraud-retractions.html. Published October 15, 2018. Accessed September 25, 2019.
  28. Kaiser J (2018) Suspect science leads to pause in stem cell trial. Science 362, 513 https://doi.org/10.1126/science.362.6414.513
  29. Epstein JA (2019) A Time to Press Reset and Regenerate Cardiac Stem Cell Biology. JAMA Cardiol 4, 95-96 https://doi.org/10.1001/jamacardio.2018.4435
  30. Sultana N, Zhang L, Yan J et al (2015) Resident c-kit(+) cells in the heart are not cardiac stem cells. Nat Commun 6, 8701 https://doi.org/10.1038/ncomms9701
  31. Rege TA and Hagood JS (2006) Thy-1, a versatile modulator of signaling affecting cellular adhesion, proliferation, survival, and cytokine/growth factor responses. Biochim Biophys Acta 1763, 991-999 https://doi.org/10.1016/j.bbamcr.2006.08.008
  32. Forte E, Miraldi F, Chimenti I et al (2012) TGFbeta-dependent epithelial-to-mesenchymal transition is required to generate cardiospheres from human adult heart biopsies. Stem Cells Dev 21, 3081-3090 https://doi.org/10.1089/scd.2012.0277
  33. Heikinheimo M, Scandrett JM and Wilson DB (1994) Localization of transcription factor GATA-4 to regions of the mouse embryo involved in cardiac development. Dev Biol 164, 361-373 https://doi.org/10.1006/dbio.1994.1206
  34. Yilbas AE, Hamilton A, Wang Y et al (2014) Activation of GATA4 gene expression at the early stage of cardiac specification. Front Chem 2, 12
  35. Akazawa H and Komuro I (2005) Cardiac transcription factor Csx/Nkx2-5: Its role in cardiac development and diseases. Pharmacol Ther 107, 252-268 https://doi.org/10.1016/j.pharmthera.2005.03.005
  36. Oldershaw R, Owens WA, Sutherland R et al (2019) Human Cardiac-Mesenchymal Stem Cell-Like Cells, a Novel Cell Population with Therapeutic Potential. Stem Cells Dev 28, 593-607 https://doi.org/10.1089/scd.2018.0170
  37. Lo Sicco C, Reverberi D, Balbi 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 https://doi.org/10.1002/sctm.16-0363
  38. Hernan GK, Nahuel AG, Imelda O et al (2017) Hypoxia inducible factor-1apotentiates jagged1-mediated angiogenesis by mesenchymal stemcell-derived exosome. Stem Cells 35, 1747-1759 https://doi.org/10.1002/stem.2618
  39. Gray WD, French KM, Ghosh-Choudhary S et al (2015) Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 116, 255-263 https://doi.org/10.1161/CIRCRESAHA.116.304360