Abstract
Both stem cell chemokine stromal cell-derived factor-1α (SDF-1α) and extracellular nucleotides such as adenosine triphosphate (ATP) are increased in ischemic myocardium. Since ATP has been reported to influence cell migration, we analysed the migratory response of bone marrow cells towards a combination of SDF-1 and ATP. Total nucleated cells (BM-TNCs) were isolated from bone marrow of cardiac surgery patients. Migration assays were performed in vitro. Subsequently, migrated cells were subjected to multicolor flow cytometric analysis of CD133, CD34, CD117, CD184, CD309, and CD14 expression. BM-TNCs migrated significantly towards a combination of SDF-1 and ATP. The proportions of CD34+ cells as well as subpopulations coexpressing multiple stem cell markers were selectively enhanced after migration towards SDF-1 or SDF-1 + ATP. After spontaneous migration, significantly fewer stem cells and CD184+ cells were detected. Direct incubation with SDF-1 led to a reduction of CD184+ but not stem cell marker-positive cells, while incubation with ATP significantly increased CD14+ percentage. In summary, we found that while a combination of SDF-1 and ATP elicited strong migration of BM-TNCs in vitro, only SDF-1 was responsible for selective attraction of hematopoietic stem cells. Meanwhile, spontaneous migration of stem cells was lower compared to BM-TNCs or monocytes.
Highlights
The contribution of bone marrow cells to cardiac regeneration has been shown by Asahara et al [1], and, to enhance the efficacy of this physiological mechanism, transplantation of bone marrow cells has since been performed in multiple experimental and clinical studies [2,3,4,5,6,7]
Since adenosine triphosphate (ATP) has been reported to influence cell migration, we analysed the migratory response of bone marrow cells towards a combination of SDF-1 and ATP
Migrated cells were subjected to multicolor flow cytometric analysis of CD133, CD34, CD117, CD184, CD309, and CD14 expression
Summary
The contribution of bone marrow cells to cardiac regeneration has been shown by Asahara et al [1], and, to enhance the efficacy of this physiological mechanism, transplantation of bone marrow cells has since been performed in multiple experimental and clinical studies [2,3,4,5,6,7]. As the retention of transplanted cells in the myocardium is limited [8] and targeting is crucial for therapeutical effect, approaches to understand and manipulate homing of cells towards sites of injury are of high importance. Among the known factors recruiting bone marrow cells to the heart, SDF-1, a chemokine ligand of the G protein coupled receptor CD184 (CXCR-4), is the most prominent. SDF-1 guides the homing of circulating hematopoietic stem cells towards their bone marrow niches [9]. SDF-1 was demonstrated to be upregulated in rat hearts as early as one hour after induction of ischemia by LAD ligation [12]. The level of SDF-1 is increased sevenfold [13]. Abbott et al demonstrated that SDF-1 upregulation after myocardial infarction is necessary for cardiac recruitment of bone marrow cells in a mouse model [14]
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