Mechanisms of DiseaseEffect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy
Introduction
Acute myocardial infarction is the most common cause of morbidity and mortality in more developed countries. Therapeutic advances have mainly been targeted at restoring antegrade perfusion in the infarct-related artery, but there seems to be a ceiling of benefit.1 Thus, in a substantial proportion of patients who experience acute myocardial infarction, congestive heart failure subsequently develops largely as a result of left-ventricular remodelling. This process involves myocardial thinning, dilation, and decreased function, and it ultimately leads to death.2, 3 One novel way to treat this process after myocardial infarction is cell therapy.4 Cellular transplantation has focused on use of various cell types, including differentiated cells such as skeletal myoblasts, cardiac myocytes, smooth-muscle cells, cardiac fibroblasts, and bone-marrow-derived cells.5, 6, 7, 8, 9, 10
There is increasing evidence that stem-cell mobilisation to the heart and differentiation into cardiac myocytes is a naturally occurring process.11, 12 However, it occurs too slowly for there to be meaningful recovery of left-ventricular function after myocardial infarction.11 Findings of some studies have shown the possibility of regenerating damaged myocardium either through the direct injection of stem cells into the bloodstream13 or by chemical mobilisation of stem cells from the bone marrow beginning 5 days before the myocardial infarction.14 These results have shown that stem cells can home to the infarct zone in the period around the infarction and then differentiate into cardiac myocytes.
Studies to date have been focused on the ability of stem cells to regenerate myocardium within 48 h of myocardial infarction. Our aim was to investigate whether a clinically viable strategy of stem-cell mobilisation would result in stem-cell engraftment or regeneration of myocardial tissue at a time remote (weeks) from myocardial infarction and after development of ischaemic cardiomyopathy. We investigated whether a key stem-cell homing factor, stromal-cell-derived factor 1 (SDF-1), is transiently expressed by the myocardium after myocardial infarction. SDF-1 and its receptor CXCR4 are crucial for bone-marrow retention of haemopoietic stem cells15, 16 and are involved in cardiogenesis,10 migration of primordial germ cells,17 and recruitment of endothelial-cell progenitor cells to sites of ischaemic tissue.18 Furthermore, the systemic overexpression of SDF-1 can lead to stem-cell mobilisation.19, 20 Therefore, the transient expression of SDF-1 after myocardial infarction could have substantial implications for potential clinical strategies to regenerate cardiac function, since it would suggest that there is a limited time after myocardial infarction during which stem cells will naturally home to injured myocardium. We further tested whether re-expression of SDF-1 through the transplantation of genetically modified autologous cells at a time remote from myocardial infarction could offer potential therapeutic benefit.
Section snippets
Animals
The Animal Research Committee approved all animal protocols, and all animals were housed in the Association for the Assessment and Accreditation of Laboratory Animal Care animal facility of the Cleveland Clinic Foundation. Animals were anaesthetised with sodium pentobarbital, 50 mg/kg, intubated, and ventilated with room air at 80 breaths per minute with a pressure-cycled rodent ventilator (Kent Scientific Corporation, RSP1002, Torrington, CT, USA). Anterior-wall myocardial infarction was
Results
To ascertain whether stem-cell mobilisation with systemic filgrastim leads to myocardial regeneration in rats with established ischaemic cardiomyopathy, blood was sampled from the animals randomly assigned filgrastim (n=6) or saline (n=6) 5 days after the start of therapy to verify bone-marrow stimulation (leucocyte count: filgrastim group vssaline group 37·3 [SD 5·3] vs 11·8 [4·0] per μL; p<0·01). Bromodeoxyuridine was given from the final day of filgrastim administration for 14 days to label
Discussion
In this study with a combined strategy of gene transfer and stem-cell mobilisation, regeneration of myocardium in a model of ischaemic cardiomyopathy was feasible and effective. SDF-1 expression was sufficient to induce stem-cell homing to infarcted myocardial tissue and may bring about stem-cell homing in acute myocardial infarction. Stem-cell mobilisation alone did not lead to significant engraftment of circulating cells in ischaemic cardiomyopathy at a time remote from the myocardial
GLOSSARY
- myc-tag
- EQKLISEEDL (myc) peptide fused to a protein of interest allowing for an antibody made against the myc peptide to identify the protein of interest.
- real-time pcr
- High-sensitivity method for quantifying the relative amounts of RNA by measuring the increase in fluorescently labelled product with PCR each cycle.
- transfect
- Transfer genetic material into mammalian cells for expression.
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