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Editorial See related article, pages 1280 –1289 Blunting Half of the Double-Edged Sword Potential Use of Interleukin-10 to Protect Bone Marrow–Derived Cells After Myocardial Infarction Matthew L. Springer, Xiaoyin Wang D Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017 endothelial cells,15 but, at least in the case of human circulating cells, are presumed by many investigators to retain their hematopoietic nature and home to angiogenic endothelium, facilitating the proliferation of the resident endothelial cells.16 Regardless of their derivation or identity, they are generally presumed to provide a natural healing mechanism, as they are attracted to multiple signals from ischemic tissue and improve vascularity. Krishnamurthy et al14 hypothesized that interleukin-10 (IL-10), which generally exerts a limiting effect on the inflammatory response, might play a role in the survival and function of EPCs that have been naturally mobilized, or therapeutically administered, to the infarcted myocardium. On surgical induction of MI in a mouse model, EPCs were mobilized to the circulation, but in an IL-10 knockout (KO) mouse, EPC mobilization was markedly diminished and much fewer EPCs were detected in the blood. One of the basic questions that the authors asked was whether the lack of IL-10 had an impact on the source or the destination of the EPC mobilization; that is, was mobilization impaired because of a defect in the act of EPCs leaving the bone marrow, or a defect in the target infarcted heart’s ability to send the proper signals to mobilize the EPCs? Surprisingly, both appear to play a role. On the one hand, the mobilization of EPCs was restored in IL-10 KO mice that had their hematopoietic systems reconstituted with wild-type bone marrow through bone marrow transplantation, suggesting that the defect in mobilization was intrinsic to the EPCs in the bone marrow, or perhaps was due to problems in neighboring hematopoietic cells in the bone marrow niche or other hematopoietic cells playing auxiliary roles. EPCs from IL-10 KO mice exhibited increased apoptosis and reduced CXCR4 expression in response to inflammatory stimuli and were impaired in their chemotaxis toward the CXCR4 ligand, SDF-1. On the other hand, the infarcted heart in the KO mouse was not upregulating the SDF-1 that was supposed to mobilize and attract the cells. Systemic administration of SDF-1 overcame the defect. So, was the defect in the signal or in the response to the signal? Additional insight comes from observations in post– bone marrow transplantation mice that the natural response to MI resulted in better cardiac function in IL-10 KO mice having wild-type bone marrow than in wild-type mice having IL-10 KO bone marrow. Most of the evidence presented appears to implicate the EPCs themselves as mediators of the IL-10 KO defect, but the direct effect of IL-10 deficiency on SDF-1 expression in the infarcted heart suggests a more complex relationship that is not entirely clear. uring a myocardial infarction (MI), tissue damage resulting from the ischemia and subsequent reperfusion injury triggers a complex combination of cellular responses,1 much of which is bone marrow– derived. Some of these responses involve a harmful inflammatory reaction to cytokines released by dying cardiomyocytes that can exacerbate the ongoing local structural damage. Other responses are beneficial, for example, the prohealing arm of the inflammatory response that replaces the necrotic and inflamed region with a fibrous scar. Still other beneficial effects are thought to be mediated by mobilized bone marrow cells (BMCs) of multiple lineages that aid in tissue healing.2,3 Much effort has gone into harnessing this endogenous cellular response by harvesting resident or mobilized bone marrow– derived cells and administering them to post-MI hearts,4 –7 with the hope that the cells will regenerate myocardium via differentiation2,8 or will preserve at-risk myocardium by actively9 or passively10 releasing paracrine growth factors or secreting exosomes.11,12 However, the aforementioned inflammatory response can cause problems by creating an environment in the post-MI heart that may be inhospitable for naturally attracted and therapeutically administered BMCs alike. Moreover, the MI-induced inflammatory response transitions the BMCs themselves to a more proinflammatory state, interfering with their therapeutic abilities.13 In this issue of Circulation Research, Krishnamurthy and colleagues14 explore naturally occurring mechanisms of dampening the inflammatory response that could potentially augment the efficacy of cell therapy for MI. Their focus is on a particular subpopulation of BMCs, the endothelial progenitor cells (EPCs). These cells, which were originally discovered in rodents, subsequently have been more thoroughly characterized in human blood, where they are known not only as EPCs but also as circulating angiogenic cells among other identities (see cautionary note below; we will refer to them here as EPCs for consistency). These bone marrow– derived circulating cells were initially proposed to differentiate into The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology (M.L.S.), Cardiovascular Research Institute (M.L.S., X.W.), and Eli and Edythe Broad Institute of Regeneration Medicine and Stem Cell Research (M.L.S.), University of California, San Francisco, San Francisco, CA. Correspondence to Matthew L. Springer, PhD, Division of Cardiology, Box 0124, University of California, San Francisco, San Francisco, CA 94143-0124. E-mail [email protected] (Circ Res. 2011;109:1196-1198.) © 2011 American Heart Association, Inc. Circulation Research is available at http://circres.ahajournals.org DOI: 10.1161/CIRCRESAHA.111.257352 1196 Springer and Wang Non-standard Abbreviations and Acronyms BMCs EPCs IL KO MI bone marrow cells endothelial progenitor cells interleukin knockout myocardial infarction Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017 Interestingly, systemic administration of IL-10 increased the number of EPCs detected in and near capillaries, and the number of capillaries was increased, which is consistent with the proangiogenic role of EPCs. In culture, treatment of EPCs with IL-10 increased VEGF transcription, suggesting that IL-10 may play roles both in blunting the inflammatory response to preserve EPCs and in stimulating the EPCs to express angiogenic factors. One cautionary note is that, to paraphrase an old joke, if you ask five “EPC” researchers what kind of cells they study, you’ll get six answers. The term EPC is used freely in the literature to refer to monocytic cells isolated from the blood that exhibit endothelial properties, produce angiogenic factors, and do not differentiate into endothelial cells; cells from blood that differentiate into endothelial cells or perhaps always were endothelial cells; cells from the bone marrow that express a variety of specific markers; cells from cord blood; cells in the embryo, and so forth. Various groups over the years have used the term to describe their cell population of interest even if that population had little in common with the cells originally described by Asahara et al.15 Species differences are important here as well, because the cells described in the mouse bone marrow and human blood express different markers and may not be exactly the same thing. Thus, it is important to keep in mind that drawing inferences from the “EPC” literature can involve observations based on multiple and diverse cell types. Describing the properties of EPCs can be like discussing the life of “Alfred” without being clear on whether that is the fellow responsible for the Nobel Prize, the man who was the master of suspense films, or Batman’s butler. That said, the EPCs described by Krishnamurthy et al are clearly therapeutic bone marrow– derived cells whose function and survival depends, in part, on IL-10. When labeled EPCs were transplanted into the infarcted myocardium, the concurrent systemic administration of IL-10 increased the survival and retention of the EPCs in the myocardium and decreased proinflammatory cytokines and infiltration of monocytes/macrophages. While it is tempting to ponder a possible shift in balance between proinflammatory monocytes/macrophages and prohealing monocytic EPCs, the authors offer a simpler explanation that the inflammatory response is detrimental to the survival of EPCs. This reasoning would be in keeping with the concept that the post-MI heart is an inflammatory milieu that is inhospitable to otherwise therapeutic cells and lends credence to the goal of modulating that milieu to limit inflammation. However, anti-inflammatory treatment has demonstrable consequences IL-10 Protects Endothelial Progenitor Cells 1197 for the post-MI heart: by interfering with the healing arm of the inflammatory response, patients have suffered from weakening of the myocardial wall and ventricular aneurysms.17,18 This bidirectional nature of the inflammatory response is a classic double-edged sword, and approaches to blunt the harmful edge without impairing the healing edge will be important for limiting post-MI myocardial damage as well as preserving the naturally reparative functions of diverse bone marrow– derived cells. Thus, more focused inflammatory modulation remains a worthwhile goal, and the current Krishnamurthy et al study presents another reason that IL-10 has therapeutic potential in the case of MI. Sources of Funding M.L.S. is supported in part by R01 HL086917 and R21 HL097129 from the NIH/NHLBI, R21 DA031966 from the NIH/NIDA, and Innovative Research Grant 11IRG5250021 from the American Heart Association. Disclosures None. References 1. Frangogiannis NG. The immune system and cardiac repair. Pharmacol Res. 2008;58:88 –111. 2. Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, NadalGinard B, Bodine DM, Leri A, Anversa P. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A. 2001;98:10344 –10349. 3. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001;107:1395–1402. 4. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H. Intracoronary autologous bonemarrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet. 2004;364:141–148. 5. Losordo DW, Schatz RA, White CJ, Udelson JE, Veereshwarayya V, Durgin M, Poh KK, Weinstein R, Kearney M, Chaudhry M, Burg A, Eaton L, Heyd L, Thorne T, Shturman L, Hoffmeister P, Story K, Zak V, Dowling D, Traverse JH, Olson RE, Flanagan J, Sodano D, Murayama T, Kawamoto A, Kusano KF, Wollins J, Welt F, Shah P, Soukas P, Asahara T, Henry TD. Intramyocardial transplantation of autologous CD34⫹ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial. Circulation. 2007;115:3165–3172. 6. Schachinger V, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM, the R-AMII. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med. 2006;355:1210 –1221. 7. Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002;106:1913–1918. 8. Rota M, Kajstura J, Hosoda T, Bearzi C, Vitale S, Esposito G, Iaffaldano G, Padin-Iruegas ME, Gonzalez A, Rizzi R, Small N, Muraski J, Alvarez R, Chen X, Urbanek K, Bolli R, Houser SR, Leri A, Sussman MA, Anversa P. Bone marrow cells adopt the cardiomyogenic fate in vivo. Proc Natl Acad Sci U S A. 2007;104:17783–17788. 9. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med. 2005;11:367–368. 10. Yeghiazarians Y, Zhang Y, Prasad M, Shih H, Saini SA, Takagawa J, Sievers RE, Wong ML, Kapasi NK, Mirsky R, Koskenvuo J, Minasi P, Ye J, Viswanathan MN, Angeli FS, Boyle AJ, Springer ML, Grossman W. Injection of bone marrow cell extract into infarcted hearts results in functional improvement comparable to intact cell therapy. Mol Ther. 2009;17:1250 –1256. 1198 Circulation Research November 11, 2011 11. Sahoo S, Klychko E, Thorne T, Misener S, Schultz KM, Millay M, Ito A, Liu T, Kamide C, Agrawal H, Perlman H, Qin G, Kishore R, Losordo DW. Exosomes from human CD34⫹ stem cells mediate their proangiogenic paracrine activity. Circ Res. 2011;109:724 –728. 12. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4:214 –222. 13. Wang X, Takagawa J, Lam VC, Haddad DJ, Tobler DL, Mok PY, Zhang Y, Clifford BT, Pinnamaneni K, Saini SA, Su R, Bartel MJ, Sievers RE, Carbone L, Kogan S, Yeghiazarians Y, Hermiston ML, Springer ML. Donor myocardial infarction impairs the therapeutic potential of bone marrow cells by an interleukin-1-mediated inflammatory response. Sci Transl Med. 2011;3:100ra90. 14. Krishnamurthy P, Thal M, Verma S, Hoxha E, Lambers E, Ramirez V, Qin G, Losordo D, Kishore R. Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium. Circ Res. 2011;109:1280 –1289. 15. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964 –967. 16. Hirschi KK, Ingram DA, Yoder MC. 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KEY WORDS: myocardial infarction 䡲 inflammation progenitor cells 䡲 bone marrow cells 䡲 IL-10 䡲 endothelial Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017 Blunting Half of the Double-Edged Sword: Potential Use of Interleukin−10 to Protect Bone Marrow-Derived Cells After Myocardial Infarction Matthew L. Springer and Xiaoyin Wang Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017 Circ Res. 2011;109:1196-1198 doi: 10.1161/CIRCRESAHA.111.257352 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2011 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. 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