The role of CXCR4/SDF-1, CD117/SCF, and c-met/HGF chemokine signalling in the mobilization of progenitor cells and the parameters of the left ventricular function, remodelling, and myocardial perfusion following acute myocardial infarction
aw Machali
ski5asa5 Buszman3
mierski1aw Pasowicz6 Tendera1,4
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, University of Louisville, Louisville, KY, USA
3 Acute Coronary Care Unit, Silesian School of Medicine, Katowice, Poland
4 European Vascular Genomics Network
5 Department of General Pathology Pomeraniam Medical University, Szczecin, Poland
6 Center for Diagnosis and Rehabilitation of Heart and Lung Diseases, John Paul II Hospital, Kraków, Poland
* Corresponding author. Tel: +48 60 4188669; fax: +48 32 2523930. E-mail address: wojwoj{at}mp.pl
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Abstract |
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 Top Abstract Chemokine/chemokine receptor...Mobilization of CXCR4+, c-kit+,...ConclusionFundingReferences |
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Chemokines and their receptors induce the qualitative and quantitative changes of the pool of bone marrow-derived and resident cardiac stem/progenitor cells, which in turn can modulate myocardial recovery after myocardial infarction (MI). Primary role of the chemokines, such as stromal cell-derived factor-1 (SDF-1), stem cell factor (SCF), hepatocyte growth factor (HGF) and leukaemia inhibitory factor (LIF) is the mobilization and homing of the bone marrow-derived stem/progenitor cells to the infarcted myocardium. In the setting of the acute MI there is an increased expression of SDF-1, HGF, LIF in the peri-infarct zone. The most important chemokine–chemokine receptor axis is SDF-1/CXCR4 which is significantly upregulated during acute MI. It corresponds with the significant mobilization of cells expressing cardiac and endothelial markers, which also express the chemokine receptors CXCR4, c-met, CD117 and leukemia inhibitory factor receptor. Specific population of small non-haematopoietic cells expressing the CXCR4 receptor was identified, which have the capability of cardiogenic differentiation. The mobilization of stem/progenitor cells expressing the receptors for chemoattractant cytokines is significantly correlated with the improvement of left ventricular ejection fraction (LVEF) and remodelling in 1-year follow-up after the acute MI. Patients with reduced LVEF after MI have also impaired mobilization of the stem/progenitor cells. The number of circulating cells is inversely correlated with the infarct area and positively with myocardial perfusion. Also the migratory response of the endothelial progenitor cells (EPCs) to the SDF-1 gradient is positively correlated with their capability to improve the perfusion and is one of the factors that seem to determine the outcome of the progenitor cell-based therapy after acute MI.
Key Words: Stem cells • Acute coronary syndromes • Chemokines • Mobilization • Endothelial progenitor cells
There are several mechanisms by which the haematopoietic and inflammatory cytokines can influence the function and structure of the myocardium in the setting of the acute myocardial infarction (MI). Cytokines may directly affect the left ventricular (LV) function or they may induce the qualitative and quantitative changes on a pool of bone marrow-derived and resident cardiac stem/progenitor cells, which in turn modulate the myocardial recovery.1–3 Our data suggest that the population of stem/progenitor cells expressing the receptors for chemoattractant cytokines, such as stromal cell-derived factor-1 (SDF-1) and stem cell factor (SCF) are correlated with the improvement of LV ejection fraction (LVEF), remodelling, and myocardial perfusion.
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Chemokine/chemokine receptor signalling involved in stem/progenitor cell homing |
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TopAbstractChemokine/chemokine receptor...Mobilization of CXCR4+, c-kit+,...ConclusionFundingReferences |
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There are several chemoattractants that may be relevant to the progenitor cell-mediated improvement of the LV function after acute MI. Their identification may be facilitated by investigating the properties of stem/progenitor cells mobilized into the blood during the MI and expressing the respective chemokine receptors. Convincing data from the studies investigating the hypothesis of the tissue-committed stem cells (TCSC) showed that the myocardial injury leads to the mobilization of bone-marrow mononuclear cells (BMMNC) expressing cardiac and endothelial markers. Similarly, ischaemic stroke induces the release of MNC-expressing markers specific to the neural tissue. The most striking finding was that TCSC expresses the SDF-1 receptor, CXCR4.4–8 In contrast to other chemokines, having multiple receptors, SDF-1 binds exclusively to CXCR4, which is its only receptor.9 This receptor–ligand system is crucial for the homing of stem cells and repopulation of the bone marrow during embryogenesis as well as mobilization, homing of the haematopoietic stem cells to the adult bone marrow.10 Accordingly, the knock-out of the SDF-1/CXCR4 leads to the defects in the development of heart and large blood vessels.9 Growing evidence shows that interaction of SDF-1 and CXCR4 plays an important role in the trafficking and homing of the cells enriched for the markers of endothelial and cardiac commitment to the areas of tissue injury within the myocardium and arteries.
It was confirmed in the murine model of acute MI that infarcted myocardium produced mRNA for SDF-1, which could be detected as early as 6 h after coronary occlusion and reached a maximum after 48 h. The presence of SDF-1 protein in the infarct area and peri-infarct zone was confirmed by immunohistochemistry.11 Similarly, a significant upregulation of other chemoattractants, such as hepatocyte growth factor (HGF), leukaemia inhibitory factor (LIF), and vascular endothelial growth factor (VEGF) was found following MI.4,11
The production of SDF-1, LIF, and HGF was sufficient to induce migration of cells, which was abolished using the respective receptor antagonists. The populations of mononuclear cells showing most significant migration to the SDF-1 gradient were also enriched with markers of cardiac (Nkx2.5, GATA-4, MEF2C) and endothelial (VE-cadherin) commitment. The cell population showing upregulation of these markers was characterized by fluorescence-activated cell sorting (FACS) as the CXCR4+Sca-1+/lin–/CD45– cells in mice. Moreover, the CD45– cells expressed significantly higher levels of mRNA for cardiac markers than CD45+ cells and were not able to reconstitute the haematopoiesis in the lethally irradiated mice. Corresponding cell subtype in humans was identified as CD133+CXCR4+CD34+CD45–.4 We investigated the mobilization of non-haematopoietic lin–CD34+CD45–, lin–CD45–CD133+, and lin–CD45–CXCR4+ cells in patients with acute MI treated with primary percutaneous coronary intervention (PCI; n = 12). Our preliminary data confirmed the release of small non-haematopoietic stem/progenitor cells following acute MI (Figure 1).
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Data from animal studies showed that the enrichment of cardiac markers was particularly significant in the sub-population of BMMNC consisting of small non-haematopoietic cells migrating to the SDF-1 gradient. The population of BMMNC is heterogenous and isolation of cells using standard gradient centrifugation may lead to losing of small cells; hence, the migration to SDF-1 or the FACS multiparameter live cell sorting following the hypotonic lysis of the erythrocytes are the appropriate methods of their isolation. In addition, using multiparameter live cell sorting systems (FACSAria, MoFlo) allowed to isolate the very small (2–4 µm) CXCR4+ cells of unique morphology resembling the embryonic stem cells (narrow rim of the cytoplasm, large nucleus, open-type chromatin), which expressed the markers of pluripotent stem cells Oct-4, SSEA-1, Nanog, Rex-1, and were described as very small embyonic-like cells (VSEL). VSELs co-cultured with C2C12 rhabdomyosarcoma cell line start to form clusters expressing the fetal alkaline phosphatase consistent with the formation of embryoid-like bodies. Importantly, VSELs differentiated into all three germ layers including cardiomyocytes12. Population of VSELs is rare (0.02% of BMMNC) and shows a significant decrease in ageing mice. Similar cells were identified in human cord blood.13 VSELs are promising candidates for further studies of cardiac regeneration and their reactivity to chemokines facilitates cell processing.
Recently, a different population of bone marrow Oct3/4+c-kit+/–CD34-Sca1- cells was described, which is capable of differentiating into spontaneously beating cardiomyocytes expressing β-adrenergic receptors and reacting to isoproterenol. The cells expressed CXCR4 and c-kit, which is consistent with other studies showing the importance of these chemokine receptors in the trafficking of cells possessing cardiogenic potential.14
It seems that the presence of chemokine receptors particularly, CXCR4, c-met, leukemia inhibitory factor receptor and the ability to migrate towards the SDF-1, LIF, and HGF gradients identifies the population of cells expressing the pluripotent stem cells markers and capable of cardiogenic differentiation. On the other hand, ischaemic injury is associated with increased expression of SDF-1, CXCR4, HGF, and LIF activated by hypoxia-induced transcription factor (HIF-1).12
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Mobilization of CXCR4+, c-kit+, c-met+, CD133+ stem/progenitor cells, LV function, and remodelling |
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TopAbstractChemokine/chemokine receptor...Mobilization of CXCR4+, c-kit+,...ConclusionFundingReferences |
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The plasma levels of chemoattractant cytokines are elevated in patients with acute MI.2 Most of the available studies showed that the levels of VEGF are increased in MI, however the data regarding the levels of SDF-1, SCF, and HGF are somewhat less consistent. Some studies showed lower concentration of SDF-1 in patients with the infarction and subsequent significant increase after 24 h and seven days,7 in others no differences were found.15 Our data showed that the number of cells positive for CD34/CXCR4, CD34/CD117, and c-met are significantly positively correlated with left ventricular ejection fraction (LVEF) [R = 0.49 (P = 0.0012) for CD34+ cells, R = 0.48 (P = 0.0018) for CXCR4+ cells, R = 0.45 (P = 0.0043) for CD117+ cells, and R = 0.41 (P = 0.01) for c-met+ cells]. After stratification according to LVEF, we showed that patients with LVEF
40% on admission have blunted increase of CD34+CXCR4+, CD34+CD117+, and c-met+ cells in comparison with patients having LVEF > 40%. The concentrations of haematopoietic/inflammatory cytokines [granulocyte colony-stimulating factor (G-CSF), HGF, VEGF, interleukin-6, SDF-1] increased in acute MI, however they were not significantly correlated with LVEF, LV end-systolic volume (LVESV), and LV end-diastolic volume (LVEDV). Interestingly, the number of CD34/CXCR4+ cells released during MI was inversely correlated with the markers of myocardial necrosis (troponin I—R = –0.45, P = 0.02; maximum activity of CK-MB—R = –0.37, P = 0,021). Also, in patients with high levels of NT-proBNP, significantly lower number of CD34+CXCR4+ cells was observed in comparison with those having a low concentration of this marker.16 Data on acute mobilization of CXCR4+ and CD117+ cells in the MI did reveal significant correlations between the number of cells and LVEF and myocardial necrosis; however it does not provide the information on the causal link between the two phenomena. In order to assess the long-term association between the mobilization of cells and LV function and remodelling, we prospectively followed-up 55 patients admitted with acute MI and treated with primary PCI and measured the number of CD34+CXCR4+, CD34+CD117+ cells on admission, following PCI and after 1 year. We found that the number of cells mobilized during MI is positively correlated with LVEF after 1 year (R = 0.55; P < 0.03). Patients with higher number of CD34+CXCR4+ cells during the MI had also significantly more circulating cells after 1 year.17 Age is the pivotal factor in the stem cell-based approach to myocardial functional repair after the MI. Important information was obtained when we compared the groups of patients aged >50 years in comparison with younger subjects. The mobilization of stem/progenitor cells was significantly reduced in older patients.17 The reduced number of CXCR4+ cells in these patients can be the result of impaired mobilization and/or decreased number of cells in the bone marrow. We found no differences in the concentrations of SDF-1, HGF, and SCF between the age subgroups. On the other hand, isolation of the bone marrow-derived CD34+CXCR4+ cells using magnetic beads for subsequent intracoronary infusion in patients enrolled into Polish REGENT trial is less-efficient in older patients (unpublished data). Animal model of the MI showed that the bone marrow stimulation with G-CSF and SCF improved the LVEF and reduced the LV remodelling. This effect was however absent in aged rats. In addition, G-CSF/SCF treatment was significantly less effective in the reduction of cardiomyocyte apoptosis in old rats.18
The associations between the mobilization of CD34+CXCR4+ cells, LVEF, remodelling, infarct area (late enhancement), and myocardial perfusion was confirmed in the prospective follow-up of patients with acute MI using the cardiac magnetic resonance imaging (cMRI) performed 5–6 days after the infarction and 1 year later. We showed that the acute mobilization of CD34+CXCR4+ cells assessed on day 1 and after 7 days, as well as the number of circulating cells after 1 year is significantly lower in patients with LVEF 40%. No differences in the levels of SDF-1, HGF, VEGF, G-CSF, and SCF were found between the groups. The number of cells on day 1 was significantly correlated with LVEF measures in the acute phase (CD34+CXCR4+; R = 0.48, P = 0.004) and after 1 year (CD34+CXCR4+; R = 0.51, P = 0.002). There was negative correlation of CD34+CXCR4+ cell counts with the parameters of LV remodelling: LVEDV (R = –0.31, P < 0.03) and LVESV (R = –0.34, P < 0.04). In addition, the number of CD34+CXCR4+ cells mobilized during acute MI was negatively correlated with the area of delayed enhancement (R = –0.30, P < 0.03). We assessed the myocardial perfusion 5–6 days after the MI during the stress test using the intravenous infusion of adenosine (140 µg/min/kg) and at rest. The number of segments displaying impaired stress first pass perfusion was negatively correlated with the number of circulating CD34+CXCR4+ cells (R = –0.57, P < 0.05). No significant correlations were found between any of these parameters and the levels of chemokines.17
In conclusion we demonstrated in the prospective follow-up that in patients with MI, the acute mobilization of CD34+CXCR4+ and CD34+CD117+ cells is significantly correlated with important prognostic parameters, such as LVEF and remodelling as well as NT-proBNP levels. The mobilization of stem/progenitor cells was substantially blunted in patients with significantly reduced LVEF (40%) in comparison with LVEF > 40%, both in acute phase of AMI as well as 1 year later (Figure 2). Moreover, we provide preliminary data suggesting that infarct-related increase of the number of circulating CD34+CXCR4+ stem/progenitor cells is negatively correlated with myocardial perfusion deficit, infarct area, and cardiac necrosis markers. These observations have to be interpreted with caution and other factors involved with stem/progenitor cell mobilization have to be considered, such as age, coexisting diseases, medications in particular statins, as well as various other factors.5, 19 Similar to our results, the study of Leone et al.20 revealed that the number of circulating CD34+ cells measured 1 year after MI is significantly positively correlated with the improvement of LVEF and wall motion score index (WMSI) in patients treated with primary PCI. The cell counts were negatively correlated to the parameters of LV remodelling, LVEDV, and LVESV. In general, there was a trend for more significant improvement of LV contractility and remodelling in patients with more significant stem/progenitor cell mobilization early in acute MI and higher number of circulating stem cells after 1 year. Interestingly, this study showed that as much as 95% of CD34+ cells coexpressed CD45 and CD133 and approximately 50% coexpressed CXCR4 receptor.
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Studies show that mobilization of the stem/progenitor cells which express the chemokine receptors was induced by myocardial ischaemia; this created interest in the clinical application of this mechanism. The possible ways of using the SDF-1/CXCR4 axis is to augment the SDF-1 production by the ischaemic tissues or to use the populations of cells enriched in CXCR4+ progenitors. The first approach was developed by the group of S. Dimmeler. They showed that the use of focused low-energy extracorporeal shock wave leads to a significant increase of the SDF-1 expression in the rat hind-limb muscle and improved homing of the EPCs to the muscle after induction of the hind-limb ischaemia.21 Therefore, it seems to be a safe and clinically feasible way to increase the SDF-1 expression in the ischaemic tissues, in order to improve the homing of the CXCR4+ cells. On the other hand, the use of the intracoronary infusion of the selected CXCR4+ cells into the recanalized infarct-related artery may help to deliver the population of cells enriched in cardiac and endothelial markers. This hypothesis in presently under investigation in a large (200 patients) multicenter, randomized trial carried out in six sites in Poland. The study compares the efficiency of non-selected BMMNC and CXCR4+-enriched population in patients with acute MI treated with primary PCI and reduced LVEF. The LVEF, LV remodelling, perfusion, and infarct size are assessed using cMRI (REGENT Trial; ClinicalTrials.gov identifier: NCT00316381 [ClinicalTrials.gov] ).
As showed by the TOPCARE-AMI investigators, the in vitro migration capacity of human CD34+ cells induced by the gradient of SDF-1 correlates with the reduction of the infarct size after intracoronary administration in patients with acute MI.22 Also the protocol of the MNC isolation from the bone marrow can influence the cell migratory capacity to the SDF-1 and subsequently modulate the clinical outcome of the intracoronary infusion of the BMMNC as showed by Seeger et al.23 The use of Ficoll protocol was associated with the higher cell migratory response to SDF-1 than the use of Lymphoprep. The differences were attributed to the differences in the outcomes between the REPAIR-AMI and ASTAMI trials. REPAIR-AMI in which the cells had better migratory response was successful in the improvement of the LVEF in contrast to the ASTAMI trial.
Therefore, the factors that may influence the migratory capacity of CXCR4+ cells have to be identified. Mobilization of BMMNC using subcutaneous injections of G-CSF was investigated in patients with acute MI in order to improve the LV function. Some of the trials however failed to show any benefit in terms of the improved LVEF and LV remodelling.24 One of the reasons of this lack of efficiency may be the reduction of the migratory capacity of EPC associated with G-CSF. Administration of G-CSF reduced the EPC migratory response to the VEGF and SDF-1, as well as the expression of the active CXCR4 receptor assessed by the expression of extracellular domain, 6H8. This N-terminal epitope is cleaved by the protease induced by G-CSF.25
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The significance of the MI-induced mobilization of the stem/progenitor cells for the LV function remains however a hypothesis and needs further studies. Also the mechanisms by which the mobilization of endogenous bone marrow cells induced by the infarction could contribute to the repair of the myocardium remains unknown. It seems unlikely that the increase of the stem/progenitor cells alone may induce the repair of the significant volume of the myocardial muscle, given that the data from the study using radiolabelled CD34+ bone marrow cells infused in patients with acute MI showed their rapid clearance from the circulation and homed primarily to the liver, spleen, and lungs and only 1.3–2.6% of cells homed to the infracted area.26
The involvement of the chemokines and their receptors in the post-infarct chemoattraction and homing of stem/progenitor cells into the myocardium was investigated primarily in the animal models of the MI. Most of the studies in patients with acute MI reported the correlations between the elevated plasma levels of the chemokines and circulating stem/progenitor cells. The presence of the correlations is by no means a hard proof of the real biological associations. Therefore, the data from humans that reflect the statistical associations between the circulating cells, chemokines, and the parameters of LV function are hypothesis-generating and not explanatory and need further studies to confirm them.
Conflict of interest: None declared.
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This paper was supported by grant PBZ-KBN-099/P05/2003 from Polish Ministry of Science and Higher Education, European Vascular Genomics Network, and Servier Research Grant.
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