DISCOVERIES (ISSN 2359-7232),2014, January-March

CITATION:

Schuh A, Butzbach B, Curaj A, Simsekyilmaz S, Bucur O, Kanzler I, Denecke B, Konschalla S, Kroh A, Sönmez TT, Marx N, Liehn EA. Novel insights into the mechanism of cell-based therapy after chronic myocardial infarction. Discoveries 2014, Jan-Mar; 2(1): e9.
DOI: 10.15190/d.2014.1;

Submitted: December 13, 2013; Published after revision:January 30, 2014

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Novel insights into the mechanism of cell-based therapy after chronic myocardial infarction

Alexander Schuh MD (1), Britta Butzbach MD (1,2), Adelina Curaj MD (2,3,4), Sakine Simsekyilmaz PhD (2), Octavian Bucur MD (5,6), Isabela Kanzler PhD (2,7), Bernd Denecke PhD (8), Simone Konschalla (2), Andreas Kroh (2,9), Tolga Taha Sönmez MD (2,10), Nikolaus Marx MD (1), Elisa A. Liehn MD, PhD (2)*

Affiliation:
(1) Department of Cardiology and Pulmonology, Medical Faculty, RWTH Aachen University, Germany, (2) Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Germany, (3) Department of Experimental Molecular Imaging, RWTH Aachen University, Germany, (4) Victor Babes National Institute of Pathology, Bucharest, Romania, (5) Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA, (6) Department of Molecular Cell Biology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania, (7) Department of Cardiothoracic and Vascular Surgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany, (8) Interdisciplinary Centre for Clinical Research (IZKF) Aachen, RWTH Aachen University, Aachen, Germany, (9) Department of Surgery, University Hospital Aachen, Germany, (10) Department of Oral and Maxillofacial Surgery, University Hospital Aachen, Germany

*Correspondence should be addressed to: Dr. Elisa A. Liehn, Institute for Molecular Cardiovascular Research (IMCAR); RWTH Aachen, Germany; Phone: +49 241 8035983; Fax: +49 241 8082716; Email: eliehn@ukaachen.de

Abstract

Objective: Cell transplantation therapy is considered a novel and promising strategy in regenerative medicine. Recent studies point out that paracrine effects and inflammation induced by transplanted cells are key factors for the improvement of myocardial function. The present study aims at differentiating paracrine effects from inflammatory reactions after cell transplantation.

Methods and results: Therefore, in vitro induced apoptotic bodies were transplanted after myocardial infarction in a rat model. Eight weeks after transplantation, the functional results showed no improvement in left ventricular function. Histological analysis revealed no significant differences in the amount of infiltrated cells and collagen content did not differ among the four groups, which sustains the functional data. Surprisingly, angiogenesis increased in groups with apoptotic bodies derived from HUVEC and endothelial progenitor cells, but not from fibroblasts. A complex genetic analysis of apoptotic bodies indicated that miRNAs could be responsible for these changes.

Conclusion:
Our study demonstrates that inflammation is critical for scar remodelling and improvement of the heart function after cell therapy, while neoangiogenesis alone is not sufficient to improve heart function.

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References

1. Liehn EA, Zernecke A, Postea O, et al. Chemokines: inflammatory mediators of atherosclerosis. Archives of physiology and biochemistry. 2006;112:229-238.
2. Liehn EA, Postea O, Curaj A, et al. Repair after myocardial infarction, between fantasy and reality: the role of chemokines. Journal of the American College of Cardiology. 2011; 58:2357-2362.
3. Tomita S, Li RK, Weisel RD, et al. Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 1999;100: II247-256.
4. Wu J, Li J, Zhang N, et al. Stem cell-based therapies in ischemic heart diseases: a focus on aspects of microcirculation and inflammation. Basic research in cardiology. 2011;106:317-324.
5. Alexander S, Sasse A, Konschalla S, et al. Repetitive transplantation of different cell types sequentially improves heart function after infarction. Journal of cellular and molecular medicine. 2012;16:1640-1647.
6. Schuh A, Breuer S, Al Dashti R, et al. Administration of vascular endothelial growth factor adjunctive to fetal cardiomyocyte transplantation and improvement of cardiac function in the rat model. Journal of cardiovascular pharmacology and therapeutics. 2005;10:55-66.
7. Skobel E, Schuh A, Schwarz ER, et al. Transplantation of fetal cardiomyocytes into infarcted rat hearts results in long-term functional improvement. Tissue engineering. 2004;10:849-864.
8. Merx MW, Zernecke A, Liehn EA, et al. Transplantation of human umbilical vein endothelial cells improves left ventricular function in a rat model of myocardial infarction. Basic research in cardiology. 2005;100:208-216.
9. Schuh A, Kroh A, Konschalla S, et al. Myocardial regeneration by transplantation of modified endothelial progenitor cells expressing SDF-1 in a rat model. Journal of cellular and molecular medicine. 2012;16:2311-2320.
10. Schuh A, Liehn EA, Sasse A, et al. Transplantation of endothelial progenitor cells improves neovascularization and left ventricular function after myocardial infarction in a rat model. Basic research in cardiology. 2008;103:69-77.
11. Strauer BE, Steinhoff G. 10 years of intracoronary and intramyocardial bone marrow stem cell therapy of the heart: from the methodological origin to clinical practice. Journal of the American College of Cardiology. 2011;58:1095-1104.
12. van der Spoel TI, Jansen of Lorkeers SJ, Agostoni P, et al. Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovascular research. 2011;91:649-658.
13. Schuh A, Liehn EA, Sasse A, et al. Improved left ventricular function after transplantation of microspheres and fibroblasts in a rat model of myocardial infarction. Basic research in cardiology. 2009;104:403-411.
14. Halicka HD, Bedner E, Darzynkiewicz Z. Segregation of RNA and separate packaging of DNA and RNA in apoptotic bodies during apoptosis. Experimental cell research. 2000;260:248-256.
15. Williamson P, Schlegel RA. Transbilayer phospholipid movement and the clearance of apoptotic cells. Biochimica et biophysica acta. 2002;1585:53-63.
16. Zernecke A, Bidzhekov K, Noels H, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Science signaling. 2009;2:ra81.
17. Shivakumar K, Sollott SJ, Sangeetha M, et al. Paracrine effects of hypoxic fibroblast-derived factors on the MPT-ROS threshold and viability of adult rat cardiac myocytes. American journal of physiology. 2008;294:H2653-2658.
18. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature medicine. 2004;10:858-864.
19. Webster KA. Programmed death as a therapeutic target to reduce myocardial infarction. Trends in pharmacological sciences. 2007;28:492-499.
20. Hristov M, Erl W, Linder S, et al. Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro. Blood. 2004;104:2761-2766.
21. Irizarry RA, Bolstad BM, Collin F, et al. Summaries of Affymetrix GeneChip probe level data. Nucleic acids research. 2003;31:e15.
22. Gentleman RC, Carey VJ, Bates DM, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome biology. 2004;5:R80.
23. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Statistical applications in genetics and molecular biology. 2004;3:Article3.
24. Bonacchi M, Nistri S, Nanni C, et al. Functional and histopathological improvement of the post-infarcted rat heart upon myoblast cell grafting and relaxin therapy. Journal of cellular and molecular medicine. 2009;13:3437-3448.
25. Du YY, Zhou SH, Zhou T, et al. Immuno-inflammatory regulation effect of mesenchymal stem cell transplantation in a rat model of myocardial infarction. Cytotherapy. 2008;10:469-478.
26. Nakanishi C, Yamagishi M, Yamahara K, et al. Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells. Biochemical and biophysical research communications. 2008;374:11-16.
27. Perez-Ilzarbe M, Agbulut O, Pelacho B, et al. Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium. European journal of heart failure. 2008;10:1065-1072.
28. Wragg A, Mellad JA, Beltran LE, et al. VEGFR1/CXCR4-positive progenitor cells modulate local inflammation and augment tissue perfusion by a SDF-1-dependent mechanism. Journal of molecular medicine (Berlin, Germany). 2008;86:1221-1232.
29. Hahn JY, Cho HJ, Kang HJ, et al. Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. Journal of the American College of Cardiology. 2008;51:933-943.
30. Liang HL, Yi DH, Zheng QJ, et al. Improvement of heart allograft acceptability associated with recruitment of CD4+CD25+ T cells in peripheral blood by recipient treatment with granulocyte colony-stimulating factor. Transplantation proceedings. 2008;40:1604-1611.
31. Yokokura Y, Hayashida N, Okazaki T, et al. Influence of angiogenesis by implantation of bone marrow mononuclear cells in the rat ischemic heart. The Kurume medical journal. 2007;54:77-84.
32. Oh H, Bradfute SB, Gallardo TD, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proceedings of the National Academy of Sciences of the United States of America. 2003;100:12313-12318.
33. Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 2002;416:542-545.
34. Anversa P, Leri A, Kajstura J. Cardiac regeneration. Journal of the American College of Cardiology. 2006;47:1769-1776.
35. Reinecke H, Murry CE. Transmural replacement of myocardium after skeletal myoblast grafting into the heart. Too much of a good thing? Cardiovasc Pathol. 2000;9:337-344.
36. Ciulla MM, Montelatici E, Ferrero S, et al. Potential advantages of cell administration on the inflammatory response compared to standard ACE inhibitor treatment in experimental myocardial infarction. Journal of translational medicine. 2008;6:30.
37. Nahrendorf M, Swirski FK, Aikawa E, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. The Journal of experimental medicine. 2007;204:3037-3047.
38. Schwarz ER, Meven DA, Sulemanjee NZ, et al. Monocyte chemoattractant protein 1-induced monocyte infiltration produces angiogenesis but not arteriogenesis in chronically infarcted myocardium. Journal of cardiovascular pharmacology and therapeutics. 2004;9:279-289.
39. Koch KC, Schaefer WM, Liehn EA, et al. Effect of catheter-based transendocardial delivery of stromal cell-derived factor 1alpha on left ventricular function and perfusion in a porcine model of myocardial infarction. Basic research in cardiology. 2006;101:69-77.
40. Bouchentouf M, Paradis P, Forner KA, et al. Monocyte derivatives promote angiogenesis and myocyte survival in a model of myocardial infarction. Cell transplantation. 2010;19:369-386.
41. Arbustini E, Brega A, Narula J. Ultrastructural definition of apoptosis in heart failure. Heart failure reviews. 2008;13:121-135.
42. Nunez R, Sancho-Martinez SM, Novoa JM, et al. Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies. Cell death and differentiation.2010; 17:1665-1671.
43. Ruvinov E, Harel-Adar T, Cohen S. Bioengineering the Infarcted Heart by Applying Bio-inspired Materials. Journal of cardiovascular translational research. 2011; 4:559-574.
44. Burghoff S, Ding Z, Godecke S, et al. Horizontal gene transfer from human endothelial cells to rat cardiomyocytes after intracoronary transplantation. Cardiovascular research. 2008;77:534-543.
45. Ferrari G, Cook BD, Terushkin V, et al. Transforming growth factor-beta 1 (TGF-beta1) induces angiogenesis through vascular endothelial growth factor (VEGF)-mediated apoptosis. Journal of cellular physiology. 2009;219:449-458.
46. Bergsmedh A, Szeles A, Henriksson M, et al. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:6407-6411.
47. Vickers KC, Remaley AT. Lipid-based carriers of microRNAs and intercellular communication. Current opinion in lipidology. 2012;23:91-97.
48. Yoon CH, Koyanagi M, Iekushi K, et al. Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: role of cardiovascular lineage commitment. Circulation. 2010;121:2001-2011.
49. Eilken HM, Adams RH. Turning on the angiogenic microswitch. Nature medicine. 2010;16:853-854.
50. Afonyushkin T, Oskolkova OV, Bochkov VN. Permissive role of miR-663 in induction of VEGF and activation of the ATF4 branch of unfolded protein response in endothelial cells by oxidized phospholipids. Atherosclerosis. 2012;225:50-55.
51. Pencheva N, Tran H, Buss C, et al. Convergent multi-miRNA targeting of ApoE drives LRP1/LRP8-dependent melanoma metastasis and angiogenesis. Cell. 2012;151:1068-1082.
52. Bang C, Fiedler J, Thum T. Cardiovascular importance of the microRNA-23/27/24 family. Microcirculation. 2012;19:208-214.
53. Collet G, Skrzypek K, Grillon C, et al. Hypoxia control to normalize pathologic angiogenesis: potential role for endothelial precursor cells and miRNAs regulation. Vascular pharmacology. 2012;56:252-261.
54. Suarez Y, Sessa WC. MicroRNAs as novel regulators of angiogenesis. Circulation research. 2009;104:442-454.
55. Fiedler J, Jazbutyte V, Kirchmaier BC, et al. MicroRNA-24 regulates vascularity after myocardial infarction. Circulation. 2011;124:720-730.
56. Fang JH, Zhou HC, Zeng C, et al. MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression. Hepatology (Baltimore, Md. 2011;54:1729-1740.
57. Li P, Guo W, Du L, et al. microRNA-29b contributes to pre-eclampsia through its effects on apoptosis, invasion and angiogenesis of trophoblast cells. Clin Sci (Lond). 2013;124:27-40.
58. Wang XH, Qian RZ, Zhang W, et al. MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. Clinical and experimental pharmacology & physiology. 2009;36:181-188.
59. Liu Z, Yang D, Xie P, et al. MiR-106b and MiR-15b modulate apoptosis and angiogenesis in myocardial infarction. Cell Physiol Biochem. 2012;29:851-862.

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