Clenbuterol Plus Granulocyte Colony-Stimulating Factor Regulates Stem/Progenitor Cell Mobilization and Exerts Beneficial Effect by Increasing Neovascularization in Rats With Heart Failure

BackgroundTreatment of beta₂-adrenergic receptor agonists with myeloid cytokines, such as granulocyte colony-stimulating factor (G-CSF) has been reported to enhance stem/progenitor cell mobilization and proliferation in ischemic myocardium. However, whether the combination therapy of G-CSF and clenbuterol (Clen) contributes to improved left ventricular (LV) function remains uncertain. We investigated whether this combination therapy induced bone marrow–derived stem/progenitor cell mobilization, neovascularization, and altered LV function after acute myocardial infarction (MI).Methods and ResultsFollowing MI, rats were treated with single Clen, high-dose Clen, and G-CSF + Clen. We evaluated LV function and remodeling with the use of echocardiography in addition to hemodynamics 3 weeks after MI. Treatment with G-CSF + Clen increased (P < .05), compared with no treatment, LV ejection fraction 46 ± 3% vs 34 ± 2%, LV dP/dt 5,789 ± 394 mm Hg vs 4,503 ± 283 mm Hg, and the percentage of circulating CD34+ cells, appearing to correlate with improvements in LV function.ConclusionsCombination therapy improved LV function 3 weeks after MI, suggesting that G-CSF + Clen might augment stem/progenitor cell migration, contributing to tissue healing. These data raise the possibility that enhancing endogenous bone marrow–derived stem/progenitor cell mobilization may be a new treatment for ischemic heart failure after MI.     

A Meta-Analysis of Stem Cell Mobilization by Granulocyte Colony-Stimulating Factor in the Treatment of Acute Myocardial Infarction

Objective This project was aimed at evaluating the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) as an adjunctive therapy to the standard therapy [percutaneous coronary interventions (PCI) and conventional medication] after acute myocardial infarction (AMI). Methods A meta-analysis of randomized controlled trials (RCTs) of G-CSF as an adjunctive therapy to standard therapy versus standard therapy was performed. The endpoints were defined as (1) target-vessel restenosis, (2) cumulative cardiac events (CCEs) that were a combined endpoint of all-cause deaths, reinfarction, and target-vessel revascularization, and (3) the changes in left ventricular ejection fraction (LVEF) from baseline to follow-up. Results 320 patients were involved in 6 RCTs, of whom 160 were randomized to the G-CSF group and 160 to the control group. The follow-up period was 6.17 ± 3.49 months. There was no significant difference in the risk of target-vessel restenosis (P = 0.90) or CCEs (P = 0.59) between the two groups. When a pooled analysis of the changes in LVEF was performed with fixed-model effect, a significant heterogeneity was observed (P < 0.00001). The pooled analysis was thus conducted with random-model effect and did not show a significant improvement as compared to the control group (P = 0.34). A similar result was found in the sensitivity analysis based on five placebo-controlled trials involving 270 patients (P = 0.94). Conclusions G-CSF as an adjunctive therapy to standard therapy for patients with AMI may be safe. However, there is not much supporting evidence that this treatment could further improve LVEF. Since there are relatively few RCTs that meet the inclusion criteria and are heterogeneous in design, further research is required.     

Trafficking of Murine Hematopoietic Stem and Progenitor Cells in Health and Vascular Disease

Hematopoietic stem cells (HSCs) possess the unique capacity for self‐renewal and differentiation into various hematopoietic cell lineages. Here we summarize the processes that underlie their mobilization and directed migration from bone marrow into peripheral tissues and back to the bone marrow compartment. We specifically focus on the potential role of hematopoietic stem and progenitor cell (HSPC) migration in vascular diseases and review data from recent studies on mice. A better understanding of the mechanisms that guide HSPCs to vascular tissues will be critical for the development of novel therapeutic strategies to prevent or reverse cardiovascular diseases.     

Circulating Stem Cell Collection in Lymphoma and Myeloma after Mobilization with Cyclophosphamide and Granulocyte Colony-Stimulating Factor for Autologous Transplantation

We report the results of 72 leukapheresis procedures performed for autologous peripheral blood stem cell collection in 18 patients with lymphoma and myeloma, after combined mobilization with cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The numbers of mononuclear cells (MNCs), CD34+ cells and granulocyte-macrophage colony-forming units (CFU-GM) either in the peripheral circulation (preleukapheresis sample) or in the product obtained from leukapheresis (leukapheresis sample) were evaluated. A highly superior proportion of CD34+ cells (14-fold) and CFU-GM (5-fold) resulted from the mobilization therapy. CFU-GM and CD34+ cells were highly enriched with respect to all MNCs (relative recoveries: 2.13, range 0.3–41, and 1.08, range 0.2–8.5, respectively) due to an additional mobilization effect by the leukapheresis procedure. Also, a relatively strong linear correlation between the three different parameters was found in the leukapheresis product (CD34+:CFU-GM, r = 0.81; MNCs:CD34, r = 0.69; MNCs:CFU-GM, r = 0.75; CFU-GM:CD34+, and MNCs, r = 0.85). Our data suggest that the number of MNCs and CD34+ cells obtained after combined mobilization with cyclophosphamide and G-CSF can be used as predictor of the number of granulomonocytic progenitors.