Loading...
Please wait, while we are loading the content...
Similar Documents
Synergism of hematopoietic cytokines for infarct repair.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Cho, H. Yoon, Young-Sup |
| Copyright Year | 2006 |
| Abstract | Over the past few years, the field of stem cell biology and its therapeutic application in cardiovascular diseases has expanded remarkably and moved to the forefront of cardiovascular science. Promising results from experimental studies with bone marrow (BM)-derived stem or progenitor cells1–3 prompted initiation of clinical trials in ischemic heart diseases (IHD). Pilot clinical trials4,5 demonstrated that cell therapy using various BM-derived cells are safe and effective for treating IHD. The discovery that BM includes various stem cells spawned the strategy of directly mobilizing and homing BM cells into the heart to regenerate injured tissue.6 This concept is appealing because invasive procedures related to harvesting and delivering BM cells into the heart can be avoided. The strategy of mobilizing stem cells from BM was initially contrived by hematologists to accelerate recovery after cancer chemotherapy.7 A number of hematopoietic cytokines, including granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), stem cell factor (SCF), flt3 ligand (FL), and erythropoietin have been tested for mobilization and repopulation of the hematopoietic system. G-CSF is the most widely investigated hematopoietic growth factor in animals and patients. In addition to mobilizing BM cells, G-CSF induces proliferation, differentiation, and survival of hematopoietic cells. Recently, G-CSF was reported to have a direct action on nonhematopoietic cells expressing G-CSF receptors such as cardiomyocytes,8 endothelial cells,8 and neuronal cells. SCF was cloned as a ligand for c-kit.9 SCF exerts its activity at the early stages of hematopoiesis in BM and acts synergistically with CSFs. Flt3 is a receptor expressed predominantly on HSCs and progenitors and has many overlapping activities with c-kit. FL belongs to a family of hematopoietic cytokines, including SCF and macrophage colony-stimulating factor (M-CSF), that are specific for class III tyrosine kinase receptors.10 FL plays a central role in the proliferation, survival, and differentiation of early hematopoietic precursor cells. FL is usually not efficient as a single cytokine, but with G-CSF it exerts synergistic effects on mobilization and engraftment of HSCs.11 A series of experimental studies was performed to test the effects of hematopoietic cytokines on myocardial infarction (MI) with the hope that mobilized stem cells could regenerate injured heart. The first study was performed by Orlic et al,6 in which they injected G-CSF plus SCF to splenectomized MI mice before and after MI and showed improvement of cardiac function. Although this study demonstrated regenerating cardiomyocytes and vessels by BrdUrd and Ki67 immunostaining, it did not prove direct transdifferentiation of mobilized BM cells into myocardial cells. This role of G-CSF in inducing cardiac homing of BM cells to regenerate hearts was challenged by another study.8 They claimed that although G-CSF treatment is beneficial for infarct repair, the mechanism of action is different. They showed that G-CSF directly binds G-CSF receptors present on multiple myocardial cells and activated its downstream signals such as the Jak–Stat pathway, and thereby reduces myocardial apoptosis, increases angiogenesis, and favorably remodels infarcted myocardium. These promising results of experimental studies in conjunction with ease of administration led to clinical trials. Although initial phase clinical trials showed improvement of function in the groups treated with G-CSF,4,5 recent largescale, double-blind, placebo-controlled trials12,13 demonstrated that G-CSF treatment in patients with acute MI after successful revascularization had no influence on infarct size and left ventricular function. The timely study by Dawn et al14 in this issue of Circulation Research addresses several important issues with regard to infarct repair by hematopoietic cytokines. The authors examined the therapeutic efficacy and underlying mechanisms of hematopoietic cytokines in repairing acute MI. They used a more clinically relevant experimental design, ie, reperfusion after coronary occlusion, administering cytokines after reperfusion, and selecting clinically appropriate doses of cytokines. They found that a combination of G-CSF plus FL regenerated injured heart to a greater extent histopathologically and functionally than G-CSF plus SCF or G-CSF alone. In this study, G-CSF alone yielded minimal benefits, in concordance with recent clinical trials.12,13 This study also addressed the remaining question of whether mobilized cells have the ability to generate new cardiac tissues by providing direct evidence of BM-derived cardiomyocytes and vessels using GFP-BM reconstituted mice. Another advance in this field is the discovery of the role of cytokines in modulation of adhesion molecules on the mobilized HSCs (lin /Sca-1 /ckit cells). It appears that the added benefits of cytokine combination is not restricted to the quantitative increase in mobilization but also to induce qualitative changes that favor the homing of HSCs into myocardium. The underlying mechanisms are likely complex. The comprehensive study design and analysis uncovered intriguing clinicopathologic discrepancies, which may provide further mechanistic insight into the role of cytokines in infarct repair. Histologically, cardiac regeneration occurred mostly in the The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiovascular Research, Caritas St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass. Correspondence to Young-sup Yoon, MD, PhD, Division of Cardiovascular Research, Caritas St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail young.yoon@tufts.edu (Circ Res. 2006;98:990-992.) © 2006 American Heart Association, Inc. |
| Starting Page | 60 |
| Ending Page | 63 |
| Page Count | 4 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://circres.ahajournals.org/content/circresaha/98/8/990.full.pdf?download=true |
| PubMed reference number | 16645148v1 |
| Volume Number | 98 |
| Issue Number | 8 |
| Journal | Circulation research |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Administration procedure American Heart Association Apoptosis Artificial cardiac pacemaker Blood Vessel Bone Marrow Cardiovascular Diseases Circumference Clone Cells Colony-Stimulating Factors Coronary Occlusion Editorial Email FLT3 wt Allele Filgrastim Gonadotropin-Releasing Hormone Receptor Granulocyte-Macrophage Colony-Stimulating Factor Green Fluorescent Proteins Heart Diseases Hematopoiesis Hematopoietic Cell Growth Factors Hematopoietic System Hematopoietic stem cells Hypericum perforatum KIT gene Left Ventricular Function Leukemia, Myelocytic, Acute Ligands Lobular Neoplasia Mast/Stem Cell Growth Factor Receptor Kit, human Myocardial Infarction Myocardial Ischemia Myocardium Myocytes, Cardiac Natural regeneration Neoplasms Neuritis, Autoimmune, Experimental Patients Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Receptors, Colony-Stimulating Factor Recombinant Macrophage Colony-Stimulating Factor Reperfusion Therapy Stem Cell Factor Stimulation (motivation) benefit cytokine engraftment ezetimibe / Simvastatin granulocyte physical hard work sargramostim transdifferentiation |
| Content Type | Text |
| Resource Type | Article |
