Chemokine stromal derived factor 1 (SDF-1) is involved in trafficking of hematopoietic stem cells (HSCs) from the bone marrow (BM) to peripheral blood (PB) and has been found to enhance postischemia angiogenesis. This study was aimed at investigating whether SDF-1 plays a role in differentiation of BM-derived c-kit ؉ stem cells into endothelial progenitor cells (EPCs) and in ischemia-induced trafficking of stem cells from PB to ischemic tissues. We found that SDF-1 enhanced EPC number by promoting ␣ 2 , ␣ 4 , and ␣ 5 integrinmediated adhesion to fibronectin and collagen I. EPC differentiation was reduced in mitogen-stimulated c-kit ؉ cells, while cytokine withdrawal or the overexpression of the cyclin-dependent kinase (CDK) inhibitor p16 INK4 restored such differentiation, suggesting a link between control of cell cycle and EPC differentiation. We also analyzed the time course of SDF-1 expression in a mouse model of hind-limb ischemia. Shortly after femoral artery dissection, plasma SDF-1 levels were up-regulated, while SDF-1 expression in the bone marrow was down-regulated in a timely fashion with the increase in the percentage of PB progenitor cells. An increase in ischemic tissue expression of SDF-1 at RNA and protein level was also observed. Finally, using an in vivo assay such as injection of matrigel plugs, we found that SDF IntroductionIt has been shown that endothelial progenitor cells (EPCs) play a role in vascular repair following ischemic injury. 1 EPCs give rise to endothelial-like cells in culture, growing as spindleshaped cells attaching to culture dishes coated with extracellular matrix (ECM) components. 2 However, the mechanisms driving EPC differentiation are largely unknown. Stromal-derived factor 1 (SDF-1) regulates adhesion/chemotaxis of bone marrow hematopoietic progenitor cells through activation/regulation of specific integrin molecules. [3][4][5] This factor is, therefore, suggested to play a major role in successful hematopoietic stem cell (HSC) engraftment in the bone marrow. 6 In vivo gene inactivation of SDF-1 and its receptor C-X-C chemokine receptor 4 in mice led to early embryonic lethality due to abnormal cerebellar, gastrointestinal vasculature, and hematopoiesis development. [7][8][9] A role for SDF-1 in HSC/EPC recruitment from bone marrow (BM) to peripheral blood (PB) has been proposed, based on the evidence that granulocyte colony stimulating factor (G-CSF)-mediated HSC/EPC mobilization causes an imbalance between the expression of BM SDF-1 and CXCR4 in HSCs, 10 and that SDF-1␣ adenovirus gene transfer enhances the number of circulating HSCs/EPCs. [11][12][13] Recently, overexpression of SDF-1 in ischemic tissues has been found to enhance EPC recruitment from PB and to induce neoangiogenesis. 14,15 In this paper, we show that SDF-1 increases EPC number through enhancement of (BM) c-kit ϩ stem cell adhesion onto extracellular matrix components by integrin receptors. Further, we show that treatment of c-kit ϩ cells with mitogenic cytokines abolished SDF-1-mediated EPC differen...

No abstract

Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.