Hematopoietic cytokines for cardiac repair: mobilization of bone marrow cells and beyond.
ABSTRACT Hematopoietic cytokines, traditionally known to influence cellular proliferation, differentiation, maturation, and lineage commitment in the bone marrow, include granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, stem cell factor, Flt-3 ligand, and erythropoietin among others. Emerging evidence suggests that these cytokines also exert multifarious biological effects on diverse nonhematopoietic organs and tissues. Although the precise mechanisms remain unclear, numerous studies in animal models of myocardial infarction (MI) and heart failure indicate that hematopoietic cytokines confer potent cardiovascular benefits, possibly through mobilization and subsequent homing of bone marrow-derived cells into the infarcted heart with consequent induction of myocardial repair involving multifarious mechanisms. In addition, these cytokines are also known to exert direct cytoprotective effects. However, results from small-scale clinical trials of G-CSF therapy as a single agent after acute MI have been discordant and largely disappointing. It is likely that cardiac repair following cytokine therapy depends on a number of known and unknown variables, and further experimental and clinical studies are certainly warranted to accurately determine the true therapeutic potential of such therapy. In this review, we discuss the biological features of several key hematopoietic cytokines and present the basic and clinical evidence pertaining to cardiac repair with hematopoietic cytokine therapy.
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ABSTRACT: Several studies suggest that circulating bone marrow derived stem cells promote the regeneration of ischemic tissues. For hematopoietic stem cell transplantation combinatorial granulocyte-colony stimulating factor (G-CSF)/Plerixafor (AMD3100) administration was shown to enhance mobilization of bone marrow derived stem cells compared to G-CSF monotherapy. Here we tested the hypothesis whether combinatorial G-CSF/AMD3100 therapy has beneficial effects in cardiac recovery in a mouse model of myocardial infarction.PLoS ONE 08/2014; 9(8):e104644. · 3.53 Impact Factor
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ABSTRACT: Background Cardiac regenerative responses are responsive to paracrine factors. We hypothesize that chronic heart failure (HF) in pediatric patients affects cardiac paracrine signaling relevant to resident c-kitposCD34neg stem cells (CSCs). Methods Discarded atrial septum (huAS) and atrial appendages (huAA) from pediatric patients with (huAA-HF; n=10) or without (huAA; n=3) HF were explant cultured suspended in media (SEC). Conditioned media was screened for 120 human factors using unedited monoclonal antibody-based arrays. Significantly expressed (relative chemiluminescence > 30/100) factors are reported (secretome). Emigrated cells were immuno-selected for c-kit and enumerated as CSCs. Results After culture Day 7, CSCs emigrate from huAA, but not huAS. The huAA secretome during CSC emigration included HGF, ENA-78/CXCL5, GRO-α/CXCL1 and MIF, candidate pro-migratory factors not present in the huAS secretome. Survival/proliferation of emigrated CSCs required co-culture with cardiac tissue or tissue- conditioned media. Removal of huAA (Day 14) resulted both in the loss of all emigrated CSCs (Day 28) and decreased expression of 13 factors including HGF, ENA-78/CXCL5, uPAR/CD87 and NAP-2/CXCL7, candidate pro-survival factors. Secretomes of atrial appendages from HF patients have lower expression of 14 factors, including HGF, ENA-78/CXCL5, GRO-α/CXCL1, MIF, NAP-2/CXCL7, uPAR/CD87 and MIP-1α, compared to atrial appendages from patients without HF. Conclusions SEC models paracrine and innate CSC interactions in heart. In pediatric patients, heart failure has an enduring effect on the ex-vivo cardiac-derived secretome with lower expression of candidate pro-migratory and pro-survival factors for CSCs.The Journal of Heart and Lung Transplantation 07/2014; · 5.61 Impact Factor
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ABSTRACT: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are valuable platforms for new therapies based on regenerative medicine. BM-MSCs era is coming of age since the potential of these cells is increasingly demonstrated. In fact, these cells give origin to osteoblasts, chondroblasts, and adipocyte precursors in vitro, and they can also differentiate versus other mesodermal cell types like skeletal muscle precursors and cardiomyocytes. In our short review, we focus on the more recent manipulations of BM-MSCs toward skeletal and heart muscle differentiation, a growing field of obvious relevance considering the toll of muscle disease (i.e., muscular dystrophies), the heavier toll of heart disease in developed countries, and the still not completely understood mechanisms of muscle differentiation and repair.BioMed Research International 01/2014; 2014:762695. · 2.71 Impact Factor