Stem cell highways: signalling beats trafficking?

After the oocyte is fertilized, the resulting one-cell zygote gives rise to all stem cell progenies. During the developmental process, these cells are necessary to generate all specialized tissues. However, some of them elude the specification cues and remain quiescent in the adult tissue, as long as the organism does not suffer from injury, illness, or specific cell-type depletion. Most adult stem cells are quiescent, others, such as the intestinal stem cells, are very active and feature intense selfrenewal kinetics. Nevertheless, when these adult stem cells are awakened by an injury or alerted upon the body’s request, they need to move on and reach the damaged area using special routs known as cellular highways (Figure 1). The more advanced the illness, the less the number of stem cells remaining in stock. Their ability to migrate effectively into damaged or diseased tissues makes the stem cells promising candidates for cell therapy. Unfortunately, cellular highways can also be used by cancer (stem-) cells during metastasis, e.g. when CXCR4-expressing tumour cells migrate into the lung, liver, bone marrow, and brain, matching high levels of presented SDF-1a. Fortunato et al. explore the SDF-1a/CXCR4 cellular highway in the context of cardiac damage, highlighting the correlation between SDF-1a plasma concentration and the migration ability of CXCR4+ circulating progenitor cells. In a prospective observational study in 172 consecutive patients with an acute coronary syndrome, of which the majority (83%) presented with ST-elevation myocardial infarction (MI), the authors correlate functional characteristics of circulating progenitor cells, antigenically defined as CD34/CD45/CD133/CXCR4 cells, with a clinical outcome up to 1 year. When categorizing the study population into patients who developed acombined event (death, recurrent MI, or newonset heart failure) during the 1-year follow-up and those without an event, the authors observed reduced spontaneous mobility of these progenitor cells in an in vitro migration assay. Moreover, they report somewhat higher serum SDF-1a levels in patients with a subsequent event, although the significance of the latter is uncertain in view of the substantial variability in serum levels and the low number of these patients (n 1⁄4 30/172 or 13.4%). Stem cells home towards acutely damaged myocardium following systemic injection, although the molecular mechanism of this process is largely unknown. Migration towards damaged tissue is the first step in stem cell engagement during tissue regeneration. Chemokines and their receptors dramatically influence the pool of circulating and resident cardiac progenitor cells, which in turn promote tissue regeneration and recovery after MI. Stromal cell-derived factor-1a (SDF-1a), stem cell factor (SCF), hepatocyte growth factor (HGF), and leukaemia inhibitory factor (LIF) are primarily involved in the mobilization and homing of the circulating progenitor cells towards the infarcted heart. Several authors, including Fortunato et al., have confirmed the importance of the chemokine–chemokine receptor axis SDF-1a/CXCR4 (reviewed in Cencioni et al.), which is stimulated during acute cardiac damage. In fact, many circulating progenitors highly express the chemokine receptors CXCR4, besides c-Met, CD117 (SCF receptor), and leukaemia inhibitory factor receptor. Local injection of SCF improves myocardial homing of systemically delivered progenitor cells. Since tissue or systemic injection of these potent chemokines could determine a dramatic change on the tissue homeostasis, ex vivo priming of progenitor cells with SDF-1a before transplantation has been challenged by several independent groups. Exposure to 100 ng/mL SDF-1a for 30 min induced proangiogenic phenotype in CD34+ circulating progenitor cells (PCs), resulting in cell migration and differentiation into vascular cords. Exposure of cardiac mesoangioblasts, vessel-associated stem cells expressing CD31, CD34, CD44, CD117, and CD146, but not CD45 and CD133, to SDF-1a improves up to five-fold their homing to the infarcted heart free wall. The authors also showed that this treatment improves cardiac regeneration and the recovery of the left ventricular (LV) wall motion. In summary, SDF-1a pre-conditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. CXCR7 also shows high-affinity binding to SDF-1a and has a more restricted surface expression, mainly in tumour cells and endothelial progenitors. Although its role in calcium mobilization and chemotaxis is still controversial, it seems that CXCR4 is required for mesenchymal stem cell (MSC) migration and adhesion, whereas CXCR7 is responsible for MSC adhesion and survival. The fact that CXCR7 function depends on the cell type, is evident in the migration ability of renal progenitor cells. Although this phenomenon required the presence of both CXCR4 and CXCR7, only CXCR7 seems to be essential in renal progenitors in order to adhere to the endothelial cells. It is interesting to note that CXCR7 has been shown to internalize and degrade SDF-1 as a ligand scavenger, which could modulate the functioning of CXCR4 in PCs of Fortunato et al. clinical study.