Potential of mesenchymal- and cardiac progenitor cells for therapeutic targeting of B-cells and antibody responses in end-stage heart failure

Autoři: Patricia van den Hoogen aff001;  Saskia C. A. de Jager aff001;  Emma A. Mol aff001;  Arjan S. Schoneveld aff003;  Manon M. H. Huibers aff004;  Aryan Vink aff004;  Pieter A. Doevendans aff006;  Jon D. Laman aff009;  Joost P. G. Sluijter aff001
Působiště autorů: Laboratory of Experimental Cardiology, UMC Utrecht Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, the Netherlands aff001;  Laboratory of Cardiovascular Cell Biology, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands aff002;  Laboratory of Clinical Chemistry & Haematology, ARCADIA, University Medical Center Utrecht, Utrecht, the Netherlands aff003;  Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands aff004;  Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands aff005;  Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands aff006;  Netherlands Heart Institute, Utrecht, the Netherlands aff007;  Central Military Hospital, Utrecht, the Netherlands aff008;  Department of Biomedical Sciences of Cells and Systems (BSCS), University Medical Center Groningen, Groningen, the Netherlands aff009
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0227283


Upon myocardial damage, the release of cardiac proteins induces a strong antibody-mediated immune response, which can lead to adverse cardiac remodeling and eventually heart failure (HF). Stem cell therapy using mesenchymal stromal cells (MSCs) or cardiomyocyte progenitor cells (CPCs) previously showed beneficial effects on cardiac function despite low engraftment in the heart. Paracrine mediators are likely of great importance, where, for example, MSC-derived extracellular vesicles (EVs) also show immunosuppressive properties in vitro. However, the limited capacity of MSCs to differentiate into cardiac cells and the sufficient scaling of MSC-derived EVs remain a challenge to clinical translation. Therefore, we investigated the immunosuppressive actions of endogenous CPCs and CPC-derived EVs on antibody production in vitro, using both healthy controls and end-stage HF patients. Both MSCs and CPCs strongly inhibit lymphocyte proliferation and antibody production in vitro. Furthermore, CPC-derived EVs significantly lowered the levels of IgG1, IgG4, and IgM, especially when administered for longer duration. In line with previous findings, plasma cells of end-stage HF patients showed high production of IgG3, which can be inhibited by MSCs in vitro. MSCs and CPCs inhibit in vitro antibody production of both healthy and end-stage HF-derived immune cells. CPC-derived paracrine factors, such as EVs, show similar effects, but do not provide the complete immunosuppressive capacity of CPCs. The strongest immunosuppressive effects were observed using MSCs, suggesting that MSCs might be the best candidates for therapeutic targeting of B-cell responses in HF.

Klíčová slova:

Antibodies – Heart failure – Immune response – Immunosuppressives – Lymphocyte proliferation – Mesenchymal stem cells – Stem cells – Antibody production


1. Wilkins E, L. W, Wickramasinghe K, P B. European Cardiovascular Disease Statistics 2017. European Heart Network. 2017.

2. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth universal definition of myocardial infarction (2018). Russ J Cardiol. 2019;24: 107–138.

3. Zhang M, Alicot EM, Chiu I, Li J, Verna N, Vorup-Jensen T, et al. Identification of the target self-antigens in reperfusion injury. J Exp Med. 2006;203: 141–52. doi: 10.1084/jem.20050390 16390934

4. O’Donohoe TJ, Schrale RG, Ketheesan N. The role of anti-myosin antibodies in perpetuating cardiac damage following myocardial infarction. Int J Cardiol. 2016;209: 226–33. doi: 10.1016/j.ijcard.2016.02.035 26897075

5. Ong S-B, Hernández-Reséndiz S, Crespo-Avilan GE, Mukhametshina RT, Kwek X-Y, Cabrera-Fuentes HA, et al. Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther. 2018;186: 73–87. doi: 10.1016/j.pharmthera.2018.01.001 29330085

6. Frangogiannis NG. The immune system and the remodeling infarcted heart: cell biological insights and therapeutic opportunities. J Cardiovasc Pharmacol. 2014;63: 185–95. doi: 10.1097/FJC.0000000000000003 24072174

7. Sattler S, Fairchild P, Watt FM, Rosenthal N, Harding SE. The adaptive immune response to cardiac injury-the true roadblock to effective regenerative therapies? NPJ Regen Med. 2017;2: 19. doi: 10.1038/s41536-017-0022-3 29302355

8. Anzai T. Inflammatory mechanisms of cardiovascular remodeling. Circ J. 2018;82: 629–635. doi: 10.1253/circj.CJ-18-0063 29415911

9. Caforio ALP, Daliento L, Angelini A, Bottaro S, Vinci A, Dequal G, et al. Autoimmune myocarditis and dilated cardiomyopathy: focus on cardiac autoantibodies. Lupus. 2005;14: 652–5. doi: 10.1191/0961203305lu2193oa 16218460

10. Eriksson U, Penninger JM. Autoimmune heart failure: new understandings of pathogenesis. Int J Biochem Cell Biol. 2005;37: 27–32. 14 doi: 10.1016/j.biocel.2004.06.014 15381145

11. Madonna R, Van Laake LW, Davidson SM, Engel FB, Hausenloy DJ, Lecour S, et al. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J. 2016;37: 1789–98. doi: 10.1093/eurheartj/ehw113 27055812

12. Le T, Chong J. Cardiac progenitor cells for heart repair. Cell death Discov. 2016;2: 16052. doi: 10.1038/cddiscovery.2016.52 27551540

13. Karantalis V, Hare JM. Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res. 2015;116: 1413–30. doi: 10.1161/CIRCRESAHA.116.303614 25858066

14. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation. 2012;126: 551–68. doi: 10.1161/CIRCULATIONAHA.111.086074 22730444

15. Martin-Rendon E, Brunskill SJ, Hyde CJ, Stanworth SJ, Mathur A, Watt SM. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J. 2008;29: 1807–18. doi: 10.1093/eurheartj/ehn220 18523058

16. Hou D, Youssef EAS, Brinton TJ, Zhang P, Rogers P, Price ET, et al. Radiolabeled cell distribution after intramyocardial, intracoronary, and interstitial retrograde coronary venous delivery: Implications for current clinical trials. Circulation. 2005;112: 150–156. doi: 10.1161/CIRCULATIONAHA.104.526749 16159808

17. van den Akker F, Feyen DAM, Van Den Hoogen P, Van Laake LW, Van Eeuwijk ECM, Hoefer I, et al. Intramyocardial stem cell injection: Go(ne) with the flow. Eur Heart J. 2017;38: 184–186. doi: 10.1093/eurheartj/ehw056 28158468

18. Wei F, Wang T-Z, Zhang J, Yuan Z-Y, Tian H-Y, Ni Y-J, et al. Mesenchymal stem cells neither fully acquire the electrophysiological properties of mature cardiomyocytes nor promote ventricular arrhythmias in infarcted rats. Basic Res Cardiol. 2012;107: 274. doi: 10.1007/s00395-012-0274-4 22744762

19. Börger V, Bremer M, Ferrer-Tur R, Gockeln L, Stambouli O, Becic A, et al. Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents. Int J Mol Sci. 2017;18.

20. Rasmusson I, Le Blanc K, Sundberg B, Ringdén O. Mesenchymal stem cells stimulate antibody secretion in human B cells. Scand J Immunol. 2007;65: 336–43. doi: 10.1111/j.1365-3083.2007.01905.x 17386024

21. Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res. 2016;64: 831–40. doi: 10.1007/s12026-016-8798-6 27115513

22. Lai P, Weng J, Guo L, Chen X, Du X. Novel insights into MSC-EVs therapy for immune diseases. Biomark Res. 2019;7: 6. doi: 10.1186/s40364-019-0156-0 30923617

23. Banerjee MN, Bolli R, Hare JM. Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions. Circ Res. 2018;123: 266–287. 1217 doi: 10.1161/CIRCRESAHA.118.311217 29976692

24. Squillaro T, Peluso G, Galderisi U. Clinical Trials With Mesenchymal Stem Cells: An Update. Cell Transplant. 2016;25: 829–48. doi: 10.3727/096368915X689622 26423725

25. Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem. 2015;37: 2415–24. doi: 10.1159/000438594 26646808

26. Cha JM, Shin EK, Sung JH, Moon GJ, Kim EH, Cho YH, et al. Efficient scalable production of therapeutic microvesicles derived from human mesenchymal stem cells. Sci Rep. 2018;8: 1171. doi: 10.1038/s41598-018-19211-6 29352188

27. Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, Döbert N, et al. Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation. 2002;106: 3009–17. doi: 10.1161/01.cir.0000043246.74879.cd 12473544

28. Bao L, Meng Q, Li Y, Deng S, Yu Z, Liu Z, et al. C-Kit positive cardiac stem cells and bone marrow-derived mesenchymal stem cells synergistically enhance angiogenesis and improve cardiac function after myocardial infarction in a paracrine manner. J Card Fail. 2017;23: 403–415. doi: 10.1016/j.cardfail.2017.03.002 28284757

29. Bolli R, Hare JM, March KL, Pepine CJ, Willerson JT, Perin EC, et al. Rationale and design of the CONCERT-HF trial (combination of mesenchymal and c-kit+ cardiac stem cells as regenerative therapy for heart failure). Circ Res. 2018;122: 1703–1715. doi: 10.1161/CIRCRESAHA.118.312978 29703749

30. van den Akker F, Vrijsen KR, Deddens JC, Buikema JW, Mokry M, van Laake LW, et al. Suppression of T cells by mesenchymal and cardiac progenitor cells is partly mediated via extracellular vesicles. Heliyon. 2018;4: e00642. doi: 10.1016/j.heliyon.2018.e00642 30003150

31. Hocine HR, Brunel S, Chen Q, Giustiniani J, San Roman MJ, Ferrat YJ, et al. Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit. Stem Cells Transl Med. 2019;8: 911–924. doi: 10.1002/sctm.18-0256 30924311

32. Sebastião MJ, Menta R, Serra M, Palacios I, Alves PM, Sanchez B, et al. Human cardiac stem cells inhibit lymphocyte proliferation through paracrine mechanisms that correlate with indoleamine 2,3-dioxygenase induction and activity. Stem Cell Res Ther. 2018;9: 290. doi: 10.1186/s13287-018-1010-2 30359288

33. van den Akker F, Deddens JC, Doevendans PA, Sluijter JPG. Cardiac stem cell therapy to modulate inflammation upon myocardial infarction. Biochim Biophys Acta. 2013;1830: 2449–58. doi: 10.1016/j.bbagen.2012.08.026 22975401

34. Noort WA, Kruisselbrink AB, in’t Anker PS, Kruger M, van Bezooijen RL, de Paus RA, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol. 2002;30: 870–8. doi: 10.1016/s0301-472x(02)00820-2 12160838

35. 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: 232–43. doi: 10.1038/nprot.2008.229 19197267

36. Mol EA, Goumans M-J, Doevendans PA, Sluijter JPG, Vader P. Higher functionality of extracellular vesicles isolated using size-exclusion chromatography compared to ultracentrifugation. Nanomedicine. 2017;13: 2061–2065. doi: 10.1016/j.nano.2017.03.011 28365418

37. Lötvall J, Hill AF, Hochberg F, Buzás EI, Di Vizio D, Gardiner C, et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell vesicles. 2014;3: 26913. doi: 10.3402/jev.v3.26913 25536934

38. Franquesa M, Mensah FK, Huizinga R, Strini T, Boon L, Lombardo E, et al. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells. 2015;33: 880–91. doi: 10.1002/stem.1881 25376628

39. Efimenko AY, Kochegura TN, Akopyan ZA, Parfyonova Y V. Autologous stem cell therapy: how aging and chronic diseases affect stem and progenitor cells. Biores Open Access. 2015;4: 26–38. doi: 10.1089/biores.2014.0042 26309780

40. Charif N, Li YY, Targa L, Zhang L, Ye JS, Li YP, et al. Aging of bone marrow mesenchymal stromal/stem cells: Implications on autologous regenerative medicine. Biomed Mater Eng. 2017;28: S57–S63. doi: 10.3233/BME-171624 28372278

41. Timmers L, Pasterkamp G, de Hoog VC, Arslan F, Appelman Y, de Kleijn DP V. The innate immune response in reperfused myocardium. Cardiovasc Res. 2012;94: 276–83. doi: 10.1093/cvr/cvs018 22266751

42. Latet SC, Hoymans VY, Van Herck PL, Vrints CJ. The cellular immune system in the post-myocardial infarction repair process. Int J Cardiol. 2015;179: 240–7. doi: 10.1016/j.ijcard.2014.11.006 25464457

43. Westman PC, Lipinski MJ, Luger D, Waksman R, Bonow RO, Wu E, et al. Inflammation as a driver of adverse left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol. 2016;67: 2050–60. doi: 10.1016/j.jacc.2016.01.073 27126533

44. Cordero-Reyes AM, Youker KA, Torre-Amione G. The role of B-cells in heart failure. Methodist Debakey Cardiovasc J. 2013;9: 15–9. doi: 10.14797/mdcj-9-1-15 23519014

45. Youker K a., Assad-Kottner C, Cordero-Reyes AM, Trevino AR, Flores-Arredondo JH, Barrios R, et al. High proportion of patients with end-stage heart failure regardless of aetiology demonstrates anti-cardiac antibody deposition in failing myocardium: humoral activation, a potential contributor of disease progression. Eur Heart J. 2014;35: 1061–8. doi: 10.1093/eurheartj/eht506 24375073

46. Nussinovitch U, Shoenfeld Y. The clinical significance of anti-beta-1 adrenergic receptor autoantibodies in cardiac disease. Clin Rev Allergy Immunol. 2013;44: 75–83. doi: 10.1007/s12016-010-8228-9 21188649

47. Keppner L, Heinrichs M, Rieckmann M, Demengeot J, Frantz S, Hofmann U, et al. Antibodies aggravate the development of ischemic heart failure. Am J Physiol Heart Circ Physiol. 2018;315: H1358–H1367. doi: 10.1152/ajpheart.00144.2018 30095974

48. Noort WA, Feye D, Van Den Akker F, Stecher D, Chamuleau SAJ, Sluijter JPG, et al. Mesenchymal stromal cells to treat cardiovascular disease: strategies to improve survival and therapeutic results. Panminerva Med. 2010;52: 27–40.

49. Abumaree M, Al Jumah M, Pace R a, Kalionis B. Immunosuppressive properties of mesenchymal stem cells. Stem cell Rev reports. 2012;8: 375–92. doi: 10.1007/s12015-011-9312-0 21892603

50. Van Den Akker F, De Jager SCA, Sluijter JPG. Mesenchymal stem cell therapy for cardiac inflammation: Immunomodulatory properties and the influence of toll-like receptors. Mediators Inflamm. 2013;2013. doi: 10.1155/2013/181020 24391353

51. Davies LC, Heldring N, Kadri N, Le Blanc K. Mesenchymal stromal cell secretion of programmed death-1 ligands regulates T cell mediated immunosuppression. Stem Cells. 2017;35: 766–776. doi: 10.1002/stem.2509 27671847

52. Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther. 2011;2: 34. doi: 10.1186/scrt75 21861858

53. Carreras-Planella L, Monguió-Tortajada M, Borràs FE, Franquesa M. Immunomodulatory effect of MSC on B cells is independent of secreted extracellular vesicles. Front Immunol. 2019;10: 1288. doi: 10.3389/fimmu.2019.01288 31244839

54. Franquesa M, Hoogduijn MJ, Bestard O, Grinyó JM. Immunomodulatory effect of mesenchymal stem cells on B cells. Front Immunol. 2012;3: 212. doi: 10.3389/fimmu.2012.00212 22833744

55. Luk F, Carreras-Planella L, Korevaar SS, de Witte SFH, Borràs FE, Betjes MGH, et al. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function. Front Immunol. 2017;8: 1042. doi: 10.3389/fimmu.2017.01042 28894451

56. Asari S, Itakura S, Ferreri K, Liu C-P, Kuroda Y, Kandeel F, et al. Mesenchymal stem cells suppress B-cell terminal differentiation. Exp Hematol. 2009;37: 604–15. doi: 10.1016/j.exphem.2009.01.005 19375651

57. Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107: 367–72. doi: 10.1182/blood-2005-07-2657 16141348

58. Dick SA, Epelman S. Chronic heart failure and inflammation: what do we really know? Circ Res. 2016;119: 159–76. doi: 10.1161/CIRCRESAHA.116.308030 27340274

59. Torre-Amione G. Immune activation in chronic heart failure. Am J Cardiol. 2005;95: 3C–8C; discussion 38C-40C. doi: 10.1016/j.amjcard.2005.03.006 15925558

60. Beez CM, Haag M, Klein O, Van Linthout S, Sittinger M, Seifert M. Extracellular vesicles from regenerative human cardiac cells act as potent immune modulators by priming monocytes. J Nanobiotechnology. 2019;17: 1–18. doi: 10.1186/s12951-018-0433-3

61. Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy. 2003;5: 485–9. doi: 10.1080/14653240310003611 14660044

62. Bollini S, Gentili C, Tasso R, Cancedda R. The Regenerative Role of the Fetal and Adult Stem Cell Secretome. J Clin Med. 2013;2: 302–27. doi: 10.3390/jcm2040302 26237150

63. van Vliet P, Smits AM, de Boer TP, Korfage TH, Metz CHG, Roccio M, et al. Foetal and adult cardiomyocyte progenitor cells have different developmental potential. J Cell Mol Med. 2010;14: 861–70. doi: 10.1111/j.1582-4934.2010.01053.x 20219011

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