Circulating progenitor cells

The experimental studies using animal models as well as clinical trials involving intracoronary infusion of bone marrow-derived cells in patients demonstrated that these stem/progenitor cells have the potential to improve the function of the myocardium after the ischaemic injury [1]. In recent years much more is known about the role of autologous progenitor cells which can be found circulating in peripheral blood and reflect the reparatory mechanism of endothelium and myocardium. Evidence that migratory cells participate in the formation of virtually all cardiac structures in transplanted heart comes from work of Quaini documenting the systemic chimerism in cases in which a male patient received a heart from a female [2].
Two hypotheses explain the role of adult progenitor cells in tissue regeneration. Stem cell plasticity is associated with homing of the stem cells to the area of tissue injury and transdifferentiation into functional endothelial cells or cardiomyocytes. Alternative hypothesis involving the concept of tissue-committed stem cells is based on the observation that bone marrow harbors a heterogenous population of cells which express tissue-specific markers, eg. genes characteristic for cardiomyocytes or endothelial cells. These cells are present in peripheral blood and are attracted by cytokines to the place of tissue injury [3, 4].
Both mechanisms require the presence of the mobile pool of progenitor cells which are mobilised in the setting of endothelial injury or myocardial ischemia and subsequent homing and engraftment to the site of injury. 

Populations of progenitor cells

Endothelial progenitor cells

Endothelial precursors capable of transforming into mature, functional endothelial cells are present in the pool of peripheral mononuclear cells in circulation [5].
Recently published large prospective observational study enrolling 519 patients with angiographically confirmed coronary artery disease showed that the high number of circulating endothelial progenitor cells is associated with a low risk of CVD death, first major cardiovascular event, revascularisation and hospitalisation. In addition, the cumulative event-free survival increased in stepwise fashion with increasing baseline EPC number. Since the number of circulating EPCs reflect the mechanism for maintaining of the endothelial integrity, the measurement of the cells may help to identify patients at increased cardiovascular risk [6].
Interestingly, in healthy subjects also the number of circulating EPC shows significant correlation with the Framingham risk score and flow-mediated brachial-artery reactivity. Therefore it seems that the measurement of EPC may represent the burden of cardiovascular risk factors as well as endothelial function beyond the widely used risk markers [7].
Acute coronary syndromes are associated with increased levels of inflammatory and hematopoietic cytokines which can mobilise the progenitor cells from the bone marrow. In acute myocardial infarction there is a rapid and significant increase of the EPC number which occurs early (< 6 hours) after the onset of ischemia [8]. Such mobilisation was also noted in patients with unstable angina in which an increase of EPC number showing normal adhesive properties was correlated with C-reactive protein levels. After 3 months of follow-up the number of EPCs was reduced by 50% in comparison to baseline counts [9]. These findings give an important message because recent data from both experimental and clinical studies show that EPC can potentially be used for therapeutic angiogenesis resulting in the improvement of myocardial function. The spontaneous mobilisation of these cells in AMI and unstable angina may be an important reparatory mechanism [5].

Numerous physiological and pathological stimuli can increase the number of circulating EPC:

• Physical activity
• Limb ischemia
• Acute myocardial infarction/unstable angina
• Vascular trauma (eg. balloon dilatation)
• Atrial fibrillation
• HMG-CoA reductase inhibitors
• Estradiol
• PPAR-? agonists
• Inflammatory and hematopoietic cytokines (VEGF, erythropoietin, angiopoietin-1, G-CSF, GM-CSF, SDF-1, HGF, LIF)

Other populations of stem/progenitor cells

Different populations of non-EPC stem/progenitor cells can also be detected in the peripheral blood. The cells are identified by the immunophenotype based on the presence of certain membrane markers, eg. CD34, c-kit (CD117). Mobilisation of stem cells in AMI involves not only the endothelial progenitors but also hematopoietic, non-hematopoietic stem cells and the mesenchymal cells [8-10]. In healthy subjects and patients with stable coronary heart disease small numbers of circulating stem cells positive for CD34 and CD117 are present in the blood. In patients with AMI a significant increase of the stem cells number was observed. The time-course stem cell mobilisation is similar to endothelial progenitors (peak number of stem cells in first 6-12 hours after the symptoms onset, subsequent decrease through the 7-day follow-up with concomitant changes in the levels of cytokines involved in the inflammatory response and stem cell recruitment) [8,10]. Among them cells positive for c-kit (CD117) antigen may represent the population involved in cardiac regeneration, because according to pivotal studies of the group of Piero Anversa the so called cardiac stem cells (cells in the myocardium of an adult which can proliferate), among other markers are identified by the presence of c-kit antigen [11].

Tissue-committed stem cells

Particular populations of stem cells in the bone marrow harbors the membrane receptor CXCR4 which is a specific receptor for chemokine stromal cell-derived factor (SDF-1).  In addition, the presence of CXCR4 identifies cells showing expression of early cardiac, muscle and endothelial markers. In mice experiments it was shown that bone marrow contains pools of cells that express early cardiac lineage markers (Nkx2.5/Csx, GATA-4, and MEF2C) and the population can be mobilised by inducing the myocardial infarction. This is the first proof that postnatal bone marrow contains nonhematopoietic population of cells that express markers for cardiac differentiation [4-6]. The peak expression of cardiac markers was found at the same time as most significant increase of stem cells number was measured [12]. A Similar phenomenon seems to occur in humans in the setting of AMI [10]. The SDF-1/CXCR-4 axis seems particularly important in stem/progenitor cell homing, chemotaxis, engrafment and retention in ischaemic myocardium, because infarct border-zone (area adjacent to the myocardial necrosis) shows the presence of SDF-1 and the levels of the hemokine increases in AMI [12, 13]. 

The significance of autologous stem cells mobilisation in terms of cardiac salvage and regeneration needs to be proved in humans but it seems to be a reparative mechanism triggered early in the course of acute coronary syndromes (ACS). Also the presence of endothelial progenitor cells in the blood reflects the physiological turnover of the endothelial lining. Finally, the measurement of the number of circulating progenitor cells may reflect the efficiency of endothelial repair in humans.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.