Browse > Article
http://dx.doi.org/10.1038/s12276-018-0171-5

Adjuvant role of macrophages in stem cell-induced cardiac repair in rats  

Lim, Soo yeon (Cell Regeneration Research Center, Chonnam National University Hospital)
Cho, Dong Im (Cell Regeneration Research Center, Chonnam National University Hospital)
Jeong, Hye-yun (Cell Regeneration Research Center, Chonnam National University Hospital)
Kang, Hye-jin (Cell Regeneration Research Center, Chonnam National University Hospital)
Kim, Mi Ra (Cell Regeneration Research Center, Chonnam National University Hospital)
Cho, Meeyoung (Cell Regeneration Research Center, Chonnam National University Hospital)
Kim, Yong Sook (Cell Regeneration Research Center, Chonnam National University Hospital)
Ahn, Youngkeun (Cell Regeneration Research Center, Chonnam National University Hospital)
Publication Information
Experimental and Molecular Medicine / v.50, no.11, 2018 , pp. 1.1-1.10 More about this Journal
Abstract
Bone marrow-derived mesenchymal stem cells (BMMSCs) are used extensively for cardiac repair and interact with immune cells in the damaged heart. Macrophages are known to be modulated by stem cells, and we hypothesized that priming macrophages with BMMSCs would enhance their therapeutic efficacy. Rat bone marrow-derived macrophages (BMDMs) were stimulated by lipopolysaccharide (LPS) with or without coculture with rat BMCs. In the LPS-stimulated BMDMs, induction of the inflammatory marker iNOS was attenuated, and the anti-inflammatory marker Arg1 was markedly upregulated by coculture with BMMSCs. Myocardial infarction (MI) was induced in rats. One group was injected with BMMSCs, and a second group was injected with MIX (a mixture of BMMSCs and BMDMs after coculture). The reduction in cardiac fibrosis was greater in the MIX group than in the BMC group. Cardiac function was improved in the BMMSC group and was substantially improved in the MIX group. Angiogenesis was better in the MIX group, and anti-inflammatory macrophages were more abundant in the MIX group than in the BMMSC group. In the BMMSCs, interferon regulatory factor 5 (IRF5) was exclusively induced by coculture with macrophages. IRF5 knockdown in BMMSCs failed to suppress inflammatory marker induction in the macrophages. In this study, we demonstrated the successful application of BMDMs primed with BMMSCs as an adjuvant to cell therapy for cardiac repair.
Keywords
Citations & Related Records
연도 인용수 순위
  • Reference
1 Pandey, A. C., Lancaster, J. J., Harris, D. T., Goldman, S. & Juneman, E. Cellular therapeutics for heart failure: focus on mesenchymal stem cells. Stem Cells Int. 2017, 640108 (2017).
2 Nguyen, P. K., Rhee, J. W. & Wu, J. C. Adult stem cell therapy and heart failure, 2000 to 2016: a systematic review. JAMA Cardiol. 1, 831-841 (2016).   DOI
3 Bolli, R. 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. 122, 1703-1715 (2018).   DOI
4 Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nat. Rev. Immunol. 9, 692-703 (2009).   DOI
5 Fraccarollo, D., Galuppo, P. & Bauersachs, J. Novel therapeutic approaches to post-infarction remodelling. Cardiovasc. Res. 94, 293-303 (2012).   DOI
6 Harel-Adar, T. et al. Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair. Proc. Natl Acad. Sci. USA 108, 1827-1832 (2011).   DOI
7 Birge, R. B. et al. Phosphatidylserine is a global immunosuppressive signal in efferocytosis, infectious disease, and cancer. Cell Death Differ. 23, 962-978 (2016).   DOI
8 Frantz, S. et al. Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction. FASEB J. 27, 871-881 (2013).   DOI
9 van Amerongen, M. J., Harmsen, M. C., van Rooijen, N., Petersen, A. H. & van Luyn, M. J. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am. J. Pathol. 170, 818-829 (2007).   DOI
10 de Couto, G. et al. Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction. J. Clin. Invest. 125, 3147-3162 (2015).   DOI
11 Nemeth, K. et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat. Med. 15, 42-49 (2009).   DOI
12 Powell, R. J. et al. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol. Ther. 20, 1280-1286 (2012).   DOI
13 Ledford, K. J., Zeigler, F. & Bartel, R. L. Ixmyelocel-T, an expanded multicellular therapy, contains a unique population of M2-like macrophages. Stem Cell Res. Ther. 4, 134 (2013).   DOI
14 Ledford, K. J., Murphy, N., Zeigler, F. & Bartel, R. L. Potential beneficial effects of ixmyelocel-T in the treatment of atherosclerotic diseases. Stem Cell Res. Ther. 4, 135 (2013).   DOI
15 Henry, T. D. et al. Safety and efficacy of ixmyelocel-T: an expanded, autologous multi-cellular therapy, in dilated cardiomyopathy. Circ. Res. 115, 730-737 (2014).   DOI
16 Patel, A. N. et al. Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial. Lancet 387, 2412-2421 (2016).   DOI
17 Ericson, J. A. et al. Gene expression during the generation and activation of mouse neutrophils: implication of novel functional and regulatory pathways. PLoS ONE 9, e108553 (2014).   DOI
18 Courties, G. et al. In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. J. Am. Coll. Cardiol. 63, 1556-1566 (2014).   DOI
19 Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat. Immunol. 12, 231-238 (2011).   DOI
20 Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243-249 (2005).   DOI
21 Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147 (1999).   DOI
22 Choudry, F. et al. A randomized double-blind control study of early intracoronary autologous bone marrow cell infusion in acute myocardial infarction: the REGENERATE-AMI clinical trialdagger. Eur. Heart J. 37, 256-263 (2016).   DOI
23 Cho, D. I. et al. The optimization of cell therapy by combinational application with apicidin-treated mesenchymal stem cells after myocardial infarction. Oncotarget 8, 44281-44294 (2017).
24 Hahn, J. Y. 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. J. Am. Coll. Cardiol. 51, 933-943 (2008).   DOI
25 Hare, J. M. et al. Comparison of allogeneic vs autologous bone marrowderived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308, 2369-2379 (2012).   DOI
26 Nauta, A. J. & Fibbe, W. E. Immunomodulatory properties of mesenchymal stromal cells. Blood 110, 3499-3506 (2007).
27 Ben-Mordechai, T. et al. Macrophage subpopulations are essential for infarct repair with and without stem cell therapy. J. Am. Coll. Cardiol. 62, 1890-1901 (2013).   DOI
28 Hu, X. et al. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J. Thorac. Cardiovasc. Surg. 135, 799-808 (2008).   DOI
29 Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037-3047 (2007).   DOI
30 Leblond, A. L. et al. Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction. PLoS ONE 10, e0137515 (2015).   DOI
31 Jeong, H. Y. et al. 5-Azacytidine modulates interferon regulatory factor 1 in macrophages to exert a cardioprotective effect. Sci. Rep. 5, 15768 (2015).   DOI
32 Cho, D. I. et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp. Mol. Med. 46, e70 (2014).   DOI
33 Libby, P. Inflammation in atherosclerosis. Nature 420, 868-874 (2002).   DOI
34 Han, J. et al. Dual Roles of Graphene Oxide To Attenuate Inflammation and Elicit Timely Polarization of Macrophage Phenotypes for Cardiac Repair. ACS Nano 12, 1959-1977 (2018).   DOI
35 Sager, H. B. et al. Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ. Res. 119, 853-864 (2016).   DOI
36 Heidt, T. et al. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ. Res. 115, 284-295 (2014).   DOI
37 Sano, T. et al. Impact of cardiac progenitor cells on heart failure and survival in single ventricle congenital heart disease. Circ. Res. 122, 994-1005 (2018).   DOI
38 Lee, S. J. et al. Enhanced therapeutic and long-term dynamic vascularization effects of human pluripotent stem cell-derived endothelial cells encapsulated in a nanomatrix gel. Circulation 136, 1939-1954 (2017).   DOI