Stromal Cell-Derived Factor-1 Plays a Critical Role in Stem Cell Recruitment to the Heart After Myocardial Infarction but Is Not Sufficient to Induce Homing in the Absence of Injury
ABSTRACT After myocardial infarction (MI), bone marrow-derived cells (BMDCs) are found within the myocardium. The mechanisms determining BMDC recruitment to the heart remain unclear. We investigated the role of stromal cell-derived factor-1alpha (SDF-1) in this process.
MI produced in mice by coronary ligation induced SDF-1 mRNA and protein expression in the infarct and border zone and decreased serum SDF-1 levels. By quantitative polymerase chain reaction, 48 hours after intravenous infusion of donor-lineage BMDCs, there were 80.5+/-15.6% more BDMCs in infarcted hearts compared with sham-operated controls (P<0.01). Administration of AMD3100, which specifically blocks binding of SDF-1 to its endogenous receptor CXCR4, diminished BMDC recruitment after MI by 64.2+/-5.5% (P<0.05), strongly suggesting a requirement for SDF-1 in BMDC recruitment to the infarcted heart. Forced expression of SDF-1 in the heart by adenoviral gene delivery 48 hours after MI doubled BMDC recruitment over MI alone (P<0.001) but did not enhance recruitment in the absence of MI, suggesting that SDF-1 can augment, but is not singularly sufficient for, BDMC recruitment to the heart. Gene expression analysis after MI revealed increased levels of several genes in addition to SDF-1, including those for vascular endothelial growth factor, matrix metalloproteinase-9, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, which might act in concert with SDF-1 to recruit BMDCs to the injured heart.
SDF-1/CXCR4 interactions play a crucial role in the recruitment of BMDCs to the heart after MI and can further increase homing in the presence, but not in the absence, of injury.
- SourceAvailable from: Vahid Razban
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- "BM-MSCs were found to express particularly abundant levels of factors required for vessel stabilization , SMC migration, and matrix remodeling, such as Tgf-b, Pdgf-b, and Mmp9. In addition, these cells also expressed high levels of Ccl5 and Sdf-1a, two chemokines known to be involved in the recruitment and retention of proangiogenic macrophages and MSCs themselves (Abbott et al., 2004; Chen et al., 2008). Thus MSCs, and in particular BM-MSCs, express a cocktail of soluble factors able to enhance their retention in an autocrine manner and also attract proangiogenic cells. "
ABSTRACT: Mesenchymal stromal cells (MSCs) are defined as multipotent, self-renewing cells residing in several tissues, including the bone marrow, adipose tissue, umbilical cord blood, and placenta (Pittenger et al., 1999). These cells are defined as multipotent, as they are capable of generating different mesenchymal cell types, traditionally adipocytes, chondrocytes, and osteocytes, but also smooth muscle cells and cardiomyocytes (Makino et al., 1999 and Pittenger et al., 1999). MSCs have been at the forefront of clinical research for the therapy of cardiovascular disorders for many years. In particular, cardiac and peripheral ischemia is a leading cause of morbidity and mortality in our aging society and suffers from a lack of curative therapies (Tendera et al., 2011). In this setting, MSC transplantation has been proposed as an innovative therapy for no-option ischemic patients. Originally, the therapeutic potential of these cells was thought to arise through their putative capacity to transdifferentiate, thereby directly contributing to vasculogenesis and tissue regeneration (Quevedo et al., 2009). This attractive hypothesis led to the prompt, perhaps immature transition of the results obtained in animal models to the clinics, with the ambitious goal to regenerate ischemic tissues (Hare et al., 2009 and Tateishi-Yuyama et al., 2002). However, MSC plasticity has been later harshly questioned (Noiseux et al., 2006), and the therapeutic potential of these cells is currently considered to derive from the secretion of a variety of growth factors and cytokines exerting a paracrine, protective effect on ischemic cells (Gnecchi et al., 2012).Stem Cell Reports 02/2015; 110(3). DOI:10.1016/j.stemcr.2015.01.001 · 5.37 Impact Factor
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- "It is expressed on the surface of platelets and endothelial cells and is secreted in plasma after activation, facilitating mobilization, migration, and domiciliation of progenitor cells in ischemic tissues  . On the other hand, CXCL12 by activating several signaling pathways has been shown to induce an inflammatory response by activation of chemotaxis, cell migration, and secretion of several inflammatory biomarkers . "
ABSTRACT: Objective: Stromal derived factor-1α/CXCL12 is a chemoattractant responsible for homing of progenitor cells to ischemic tissues. We aimed to investigate the association of plasma CXCL12 with long-term cardiovascular outcomes in patients with coronary artery disease (CAD). Methods: 785 patients aged: 63 ± 12 undergoing coronary angiography were independently enrolled into discovery (N = 186) and replication (N = 599) cohorts. Baseline levels of plasma CXCL12 were measured using Quantikine CXCL12 ELISA assay (R&D systems). Patients were followed for cardiovascular death and/or myocardial infarction (MI) for a mean of 2.6 yrs. Cox proportional hazard was used to determine independent predictors of cardiovascular death/MI. Results: The incidence of cardiovascular death/MI was 13% (N = 99). High CXCL12 level based on best discriminatory threshold derived from the ROC analysis predicted risk of cardiovascular death/MI (HR = 4.81, p = 1 × 10(-6)) independent of traditional risk factors in the pooled cohort. Addition of CXCL12 to a baseline model was associated with a significant improvement in c-statistic (AUC: 0.67-0.73, p = 0.03). Addition of CXCL12 was associated with correct risk reclassification of 40% of events and 10.5% of non-events. Similarly for the outcome of cardiovascular death, the addition of the CXCL12 to the baseline model was associated with correct reclassification of 20.7% of events and 9% of non-events. These results were replicated in two independent cohorts. Conclusion: Plasma CXCL12 level is a strong independent predictor of adverse cardiovascular outcomes in patients with CAD and improves risk reclassification. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.Atherosclerosis 10/2014; 238(1):113-118. DOI:10.1016/j.atherosclerosis.2014.10.094 · 3.99 Impact Factor
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- "We speculate that this could have been a ‘false negative’ result with MK626, despite its ability to inhibit DPP-4 activity , as it is more rapidly metabolized in rodents, so exposure to the active drug may have been too low to see an effect. Moreover, only very high doses of sitagliptin (20 to 200 times higher compared to the current MK626 dosage) were shown to increase β-cell proliferation or neogenesis via the maintenance of high GLP-1 or GIP levels through DPP-4 inhibition, which can activate the phosphoinositol 3-kinase (PI3K), cyclic AMP (cAMP) and protein kinase A (PKA) signaling and cause cyclin D1/D2 activation . "
ABSTRACT: Combining immune intervention with therapies that directly influence the functional state of the β-cells is an interesting strategy in type 1 diabetes cure. Dipeptidyl peptidase-4 (DPP-4) inhibitors elevate circulating levels of active incretins, which have been reported to enhance insulin secretion and synthesis, can support β-cell survival and possibly stimulate β-cell proliferation and neogenesis. In the current study, we demonstrate that the DPP-4 inhibitor MK626, which has appropriate pharmacokinetics in mice, preceded by a short-course of low-dose anti-CD3 generated durable diabetes remission in new-onset diabetic non-obese diabetic (NOD) mice. Induction of remission involved recovery of β-cell secretory function with resolution of destructive insulitis and preservation of β-cell volume/mass, along with repair of the islet angioarchitecture via SDF-1- and VEGF-dependent actions. Combination therapy temporarily reduced the CD4-to-CD8 distribution in spleen although not in pancreatic draining lymph nodes (PLN) and increased the proportion of effector/memory T cells as did anti-CD3 alone. In contrast, only combination therapy amplified Foxp3+ regulatory T cells in PLN and locally in pancreas. These findings open new opportunities for the treatment of new-onset type 1 diabetes by introducing DPP-4 inhibitors in human CD3-directed clinical trials.PLoS ONE 09/2014; 9(9):e107935. DOI:10.1371/journal.pone.0107935 · 3.23 Impact Factor