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Transplantation of bone marrow-derived cells expressing Akt into infarcted murine heart produces dramatic improvement in cardiac function despite infrequent cellular fusion.
No full textGene and cell-based therapies for heart disease
Full text linkHeart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Recent developments in understanding the molecular mechanisms of myocardial disease have led to the identification of new therapeutic targets, and the availability of vectors with enhanced myocardial tropism offers the opportunity for the design of gene therapies for both protection and rescue of the myocardium. Genetic therapies have been devised to treat complex diseases such as myocardial ischemia, heart failure, and inherited myopathies in various animal models. Some of these experimental therapies have made a successful transition to clinical trial and are being considered for use in human patients. The recent isolation of endothelial and cardiomyocyte precursor cells from adult bone marrow may permit the design of strategies for repair of the damaged heart. Cell-based therapies may have potential application in neovascularization and regeneration of ischemic and infarcted myocardium, in blood vessel reconstruction, and in bioengineering of artificial organs and prostheses. We expect that advances in the field will lead to the development of safer and more efficient vectors. The advent of genomic screening technology should allow the identification of novel therapeutic targets and facilitate the detection of disease-causing polymorphisms that may lead to the design of individualized gene and cell-based therapies
Molecular and cell based therapies for protection, rescue and repair of ischemic myocardium: reasons for cautious optimism
Full text linkDespite the significant therapeutic advances of the past 25
years, coronary ischemic artery disease (CAD) remains the
predominant cause of premature death. The prevalence of the
disease imposes enormous financial strain on the healthcare
system calling for new approaches for treatment of CAD. The
availability of cardiotropic vectors capable of long-term and
stable protein expression and the recent isolation of progenitor
cells with regenerative and angiogenic potential may provide
opportunities for the design of novel therapies for protection and
rescue of the myocardium from ischemia and failure. Cardioprotective gene therapy strategies have been effective in animal models of myocardial ischemia and reperfusion injury, and gene transfer of proangiogenic cytokines has been used as a
strategy for rescuing ischemic myocardium. Transplantation of
autologous progenitor cells is emerging as a potential option for
the revascularization and repair of ischemic and infarcted myocardium. Notwithstanding these promising findings, there is pressing need for the development of safer and more effective vectors and the optimization and standardization of gene- and cell-based therapies.
In this article, we discuss the current preclinical and clinical advances in gene- and cell-based therapies for protection,
rescue, and repair of the ischemic myocardium, with emphasis on strategies for protection of the myocardium from ischemia and reperfusion injury and for neovascularization and regeneration of ischemic and infarcted myocardium
Endothelium targeted gene and cell based therapies for vascular diseases
No full textMost common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function. Such strategies may be useful in the treatment of chronic diseases such as hypertension, atherosclerosis, and ischemic artery disease, as well as in acute myocardial infarction and during open heart surgery for prevention of ischemia and reperfusion (I/R)-induced injury. The recent identification of putative endothelial progenitor cells in peripheral blood may allow the design of autologous cell-based strategies for neovascularization of ischemic tissues and for the repair of injured blood vessels and bioengineering of vascular prosthesis. "Proof-of-concept" for some of these strategies has been established in animal models of cardiovascular disease. However the successful translation of these novel strategies into clinical application will require further developments in vector and delivery technologies. Further characterization of the processes involved in mobilization, migration, homing, and incorporation of endothelial progenitor cells into the target tissues is necessary, and the optimal conditions for therapeutic application of these cells need to be defined and standardized
Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries
Full text linkBACKGROUND: The existence of circulating endothelial progenitor cells (CEPCs) has previously been documented. These cells can be mobilized by cytokines and are recruited to sites of injury, where they may participate in tissue repair. In the present study, we examined the hypothesis that mobilization of CEPCs by exogenous granulocyte-colony stimulating factor (G-CSF) enhances repair of injured arteries by facilitating reendothelialization and inhibiting neointima development.
METHODS AND RESULTS: Male rats were injected daily with 50 microg/kg recombinant human G-CSF or 0.9% NaCl SC for 8 days. On the fifth day of treatment, 1 mL of blood was collected for fluorescence-activated cell sorting analysis of mononuclear cells, and the animals underwent balloon angioplasty of the common carotid artery. The animals were killed at 2 or 4 weeks after injury, and the carotid arteries were harvested and processed for immunohistochemistry, scanning electron microscopy (SEM), and morphometric analysis of endothelialization and neointimal formation. G-CSF increased the number of circulating mononuclear cells that express endothelial cell lineage markers several-fold. SEM and immunohistochemical staining with the endothelial marker, platelet and endothelial cell adhesion molecule-1, showed rapid and nearly complete (>90%) reendothelialization of the denuded vessels in the G-CSF-treated animals compared with <20% in the control animals. Reendothelialization was paralleled by a decrease in inflammation in the vessel wall. Neointima thickness was reduced by approximately 60% in the G-CSF-treated animals compared with control animals at 2 and 4 weeks after injury.
CONCLUSIONS: We postulate that cytokine-induced mobilization of CEPCs may be a suitable therapeutic strategy for prevention of restenosis after revascularization procedures
Mesenchymal stem cells overexpressing Akt exhibit enhanced glucose transport and resist hypoxia induced apoptosis
No full textCytokine-mobilized bone marrow cells re-endothealize injured blood vessel and inhibit neointimal formation.
No full textBone marrow stem cells can be mobilized by cytokines such as
stem cell factor (SCF), granulocyte-colony-stimulating factor (GCSF), or vascular endothelial growth factor (VEGF). These enriched bone marrow cells in the circulation can home to the injured tissues and differentiate, thereby contribute to neovascularization and cardiac repair. In this study, we hypothesize systemic cytokine administration at the time of vascular injury mobilizes these cells to the injured blood vessel. These progenitor cells differentiate into endothelial cells, provide enhanced endothelialization, and inhibit neointimal formation. Sprague-Dawley male rats (body weight 200g) were splenectomized and 2 weeks later were injected s.c. with
recombinant human G-CSF, 50 mg/kg/day, once a day for 8 days. At the fifth day, animals were subjected to balloon angioplasty of the carotid artery, and followed by three more days of G-CSF injection. The control animals received injection of normal saline. Animals were killed at varied time points, and carotid arteries were harvested and processed for morphometric analysis, immunochemistry, scan electronic microscopy (SEM) and vascular reactivity measurement. The neointimal formation at 2 weeks after injury was significantly inhibited by 70% in the G-CSF treated animals compared to control. Staining with endothelium specific marker, PECAM-1 shows enhanced endothelialization (>90%) in the G-CSF treated arteries
compared to less than 20% in the control. SEM data further confirmed this difference of endothelium coverage between the two groups of animals. The expression of vascular cell adhesion molecule-1 (VCAM-1) was much lower in the G-CSF treated than the control. The effect of G-CSF on restoration of vascular reactivity and proliferation rate of vascular smooth muscle cell were also studied. These findings provide evidence that mobilized bone marrow cells by G-CSF effectively inhibit neointimal formation by homing to the injured site and by facilitating endothelialization, and suggest the possibility of administration of G-CSF as a simple but effective method to prevent neointimal hyperplasia
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Genetically engineered mesenchymal stem cells expressing Akt exhibit improved glucose metabolism, resistance to apoptosis and markedly improved performance of infarcted rat hearts.
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