European Heart Journal Advance Access originally published online on April 4, 2006
European Heart Journal 2006 27(9):1013-1015; doi:10.1093/eurheartj/ehi889
Interleukin-8: more on the mechanisms of progenitor cells mobilization in acute coronary syndromes
Tendera1
1 Third Division of Cardiology, Silesian School of Medicine, 45-47 Zioowa Street, 40-635 Katowice, Poland
2 Stem Cell Biology Program at James Graham Brown Cancer Center and Department of Medicine, University of Louisville, Louisville, KY 40202, USA
* Corresponding author. Tel: +48 604188669; fax: +48 32 2523930. E-mail address: wojwoj{at}mp.pl
This editorial refers to ‘Interleukin-8 is associated with circulating CD133+ progenitor cells in acute myocardial infarction’
by K. Schömig et al., on page 1032
In the article published in the current issue of European Heart Journal, Schömig and collaborators identify new humoral factor associated with the release of progenitor cells in acute myocardial infarction (AMI). The article expands current knowledge with regard to mobilization of bone-marrow progenitors in AMI by showing that parallel to already described increase of vascular endothelial growth factor, there is a marked upregulation of interleukin-8 (IL-8) in patients with AMI treated with primary percutaneous coronary intervention (PCI). The increase of IL-8 levels shows the similar time-course as the mobilization of CD133+ cells, moreover plasma concentrations of IL-8 and were shown to be an independent predictor of circulating CD133+ cells number in multivariable regression model that included parameters known to influence the progenitor cell mobilization, such as cardiovascular risk factors, infarct size, and use of statins.
Authors investigated the mobilization of three populations of circulating cells differentiated according to their immunophenotype and in vitro characteristics: endothelial progenitor cells (EPC), mature endothelial cells (EC), and less well-defined CD133+ CD34+ CD45– progenitor cells.1
EPC are capable of transforming into mature, functional EC and can be regarded as the pool of cells maintaining the integrity of vascular endothelium, as numerous studies confirmed their pivotal role in vasculogenesis and angiogenesis after ischaemic injury in the setting of AMI and peripheral artery disease.2 Shintani et al.3 were the first to describe and characterize the CD34+ mononuclear cells positive for lineage markers (KDR, VE-cadherin, CD31) as well as function (Dil-acLDL uptake) and morphology of EPC which were mobilized into peripheral blood in AMI.
These findings were subsequently confirmed and expanded by Masa et al.,4 in AMI patients and by George et al.5 in patients with unstable angina. Moreover, the authors found a positive correlation between the EPC number and systemic inflammation reflected by C-reactive protein levels.1 Inflammatory injury as well as other metabolic and haemodynamic stimuli can induce the EC apoptosis and release of endothelial microparticles expressing the EC markers (CD31, CD51, CD62E, CD146) in numbers that correspond to the degree of dysfunction of endothelium-dependent coronary artery reactivity.2,6 In addition, the number of circulating CD34+KDR+EPC can predict the risk of cardiovascular events, revascularization and hospitalization, as well as death from cardiovascular causes in patients with stable coronary artery disease (CAD).6
Trafficking of stem cells involves the mobilization into peripheral blood, homing, adhesion, and transmigration across the endothelium and engraftment into the target tissue. This process being part of inflammatory response and tissue repair requires signalling mediated primarily by chemokines, which are the most important regulators of cell trafficking, survival, and function.7 Stromal-derived factor-1, an exclusive ligand of CXCR4 receptor, is a crucial factor involved in progenitor cell mobilization and homing.7,10 As shown in animal models of AMI as well as in AMI in humans, there is an increase of SDF-1 production and release from ischaemic myocardium generating the SDF-1 gradient towards the heart. In addition, the number of circulating CXCR4+ significantly increases, early in AMI8 and ischaemic stroke.9 We have hypothesized that bone marrow harbours a heterogenous population of cells positive for CXCR4 which express genes specific e.g. for early muscle, myocardial, and EPC.7–10 These tissue-committed stem cells (TCSC) circulate in the peripheral blood at low numbers and can be mobilized by haematopoietic cytokines in the setting of vascular injury, ischaemia, and after cytokine stimulation. The homing of TCSC is also dependent on other chemokines and their receptors such as leukaemia inhibitory factor (LIF)—LIF receptor and hepatocyte growth factor—c-met axis. All mentioned mechanisms regulate the mobilization and homing of primarily non-haematopoietic cells of following immunophenotype: CXCR4+/Sca-1+/lin-/CD45– in mice and CXCR4+/CD34+/AC133+/CD45– in humans expressing early cardiac and endothelial markers to the site of myocardial injury.9,10 Recently, we obtained an evidence that murine bone marrow-derived CXCR4+/Sca-1+/lin-/CD45– express several markers of pluripotent embryonic-like stem cells. Based on their morphology and positive staining for Oct-4 and Nanog, we called them very small embryonic like stem cells. These cells could be an ideal population of stem cells for regeneration of myocardium.
Thus mobilization of stem/progenitor cells in AMI involves not only the EPC but also other less well-defined haematopoietic and non-haematopoietic progenitors expressing CXCR4, CD117, c-met, CD133 and c-met+ cells, mesenchymal cells, and pluripotent VSEL stem cells.10 In patients with AMI, the increase of stem cells number in the peripheral blood was demonstrated with parallel increase of mRNA expression for early cardiac, muscle, and endothelial markers in peripheral blood mononuclear cells.8
As the number of progenitor cells in stable CAD has significant predictive value, the obvious question is if the same is true for AMI. So far no prospective study showed an association between the clinical end-points and number of progenitor cells, however, some data suggest that mobilization of stem cells is associated with clinically important parameters of left ventricular function. When considering the data showing significant correlations between the stem/progenitor cells mobilization and left ventricular function, remodelling and infarct size, one may assume that the degree of myocardial damage influences the cell mobilization. The causal relationship can be bidirectional and further investigation of this issue is of great importance. One can assume that the large amount of ischaemic myocardium may be a potent early stimulator of cell mobilization very early on in AMI and what is measured in peripheral blood 12–24 h after the initial ischaemia is merely a remnant population of cells that already did not engraft into the myocardium. On the other hand, large area of necrosis may be the result of impaired mobilization because of the low bone marrow reserve or defective function of progenitor cells. As the data from numerous studies including large prospective observational studies indicate that number of cardiovascular risk factors is negatively correlated with the number as well as the function of EPC in patients with stable CAD, the important issue is to address this association also in patients with AMI. Based on this, Schömig et al. performed the multivariate analysis which revealed that number of CVD risk factors and use of statins were factors independently associated with EPC mobilization also in patients with AMI.1,2,6 Based upon this compelling evidence it seems that mobilization of progenitor cells should be incorporated into the profile of risk markers for CAD risk and outcomes, as the EPC mobilization and EC shedding into blood is a common link of various noxious stimuli associated with atherogenesis. This concept, however, is much better documented in patients with stable CAD than acute coronary syndromes and needs prospective evaluation in AMI. The predictive value of progenitor cells was also well established for EC and EPC and to lesser extent for other progenitor cells including TCSC. Moreover, not only the number but also the function of circulating EPC should be considered, as some data suggest the impaired function of the cells in AMI.2,6 Numerous physiological and pathological stimuli that can influence the number of circulating EPC and other progenitor cells were characterized (Table 1).
|
Regardless of fascinating and consistent data suggesting that mobilization of various populations of progenitor cells, including well-defined endothelial progenitors and novel pool of tissue committed progenitor is a coordinated and targeted reparatory mechanism rather than the generalized inflammatory reaction, one cannot ignore the growing evidence that other tissues, besides bone marrow, may contain the resident stem cells (e.g. cardiac stem cells) that may be also involved in myocardial and vascular salvage. This hypothesis does not, however, challenge the concept of the role of bone marrow-derived circulating progenitors in cardiac repair after AMI, as these two mechanisms can coexist.
The article by Schömig et al. published in the current issue of European Heart Journal confirms the previously published findings regarding the mobilization of progenitor cells in AMI and expands the knowledge about the humoral factors influencing the cell mobility.
Acknowledgement
This study was supported by grant PBZ-KBN-099/P05/2003 by Polish Ministry of Education and Science.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehi761 
References
- Schömig K, Busch G, Steppich B, Sepp D, Kaufmann J, Stein A, Schömig A, Ott I. Interleukin-8 is associated with circulating CD133+ progenitor cells in acute myocardial infarction. Eur Heart J 2006; 27: 1032–1037. First published on February 2, 2006, doi:10.1093/eurheartj/ehi761.
[Abstract/Free Full Text] - Urbich C, Dimmeler S. Endothelial progenitor cells characterization and role in vascular biology. Circ Res 2004; 95: 343.
[Abstract/Free Full Text] - Shintani S, Murohara T, Ikeda H, Ueno T, Honma T, Katoh A, Sasaki K, Shimada T, Oike Y, Imaizumi T. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001; 103: 2776–2779.
[Abstract/Free Full Text] - Massa M, Rosti V, Ferrario M, Campanelli R, Ramajoli I, Rosso R, De Ferrari GM, Ferlini M, Goffredo L, Bertoletti A, Klersy C, Pecci A, Moratti R, Tavazzi L. Increased circulating hematopoietic and endothelial progenitor cells in the early phase of acute myocardial infarction. Blood 2005; 105: 199–206.
[Abstract/Free Full Text] - George J, Goldstein E, Abashidze S, Deutsch V, Shmilovich H, Finkelstein A, Herz I, Miller H, Keren G. Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation. Eur Heart J 2004; 25: 1003–1008.
[Abstract/Free Full Text] - Werner N, Nickenig G. Influence of cardiovascular risk factors on endothelial progenitor cells limitations for therapy? Arterioscler Thromb Vasc Biol 2006; 26: 257.
[Abstract/Free Full Text] - Kucia M, Reca R, Jala VR, Dawn B, Ratajczak J, Ratajczak MZ. Bone marrow as a home of heterogenous populations of non-hematopoietic stem cells. Leukemia 2005; 19: 1118–1127.[CrossRef][Medline]
- Wojakowski W, Tendera M, Michalowska A, Majka M, Kucia M, Maslankiewicz K, Wyderka R, Ochala A, Ratajczak MZ. Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation 2004; 16: 3213–3220.
- Kucia M, Zhang YP, Reca R, Wysoczynski M, Machalinski B, Majka M, Ildstad ST, Ratajczak J, Shields CB, Ratajczak MZ. Cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following stroke. Leukemia 2006; 20: 18–28. doi:10.1038/sj.leu.2404011.
- Paczkowska E, Larysz B, Rzeuski R, Karbicka A, Jalowinski R, Kornacewicz-Jach Z, Ratajczak MZ, Machalinski B. Human hematopoietic stem/progenitor-enriched CD34(+) cells are mobilized into peripheral blood during stress related to ischemic stroke or acute myocardial infarction. Eur J Haematol 2005; 75: 461–467.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in EHJ:
- Interleukin-8 is associated with circulating CD133+ progenitor cells in acute myocardial infarction
- Kathrin Schömig, Gabriele Busch, Birgit Steppich, Dominik Sepp, Jan Kaufmann, Andreas Stein, Albert Schömig, and Ilka Ott
EHJ 2006 27: 1032-1037.[Abstract] [FREE Full Text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||