C. Zgheib1,2, J. Xu1,2, M. Allukian3, M. W. Morris2, R. C. Caskey3, J. Hu1,2, J. H. Gorman3, R. C. Gorman3, K. W. Liechty1,2 1University Of Colorado Denver,School Of Medicine – Department Of Surgery,Aurora, CO, USA 2Colorado Children’s Hospital,Department Of Surgery,Aurora, CO, USA 3University Of Pennsylvania,The Perelman School Of Medicine,Philadelphia, PA, USA
Introduction: The normal fetal response to myocardial infarction (MI) results in regeneration of functional myocardium. In contrast, the adult response results in infarct scar formation and progressive decline in cardiac function due to scar remodeling. We have shown that inhibition of stromal-derived factor-1α (SDF-1α) in the fetal infarct blocks the recruitment of cardiac progenitor cells and results in a lack of regeneration, similar to the adult response. We hypothesized that this lack of regeneration is due to fetal infarct scar formation, increased collagen gene expression, and increased collagen remodeling.
Methods: To test this hypothesis, 20% apical infarcts were created in adult and fetal sheep by LAD ligation. In a subset of fetal sheep, the infarcts were injected with a lentivirus containing the SDF-1α inhibitor transgene. Animals were harvested 3 or 30 days following infarction. Echocardiography was performed to assess cardiac function and infarct size. Histology was used to assess scar formation. Real-time PCR was used to assess collagen (Col 1α1) and matrix metalloproteinase-9 (MMP-9) gene expression.
Results: At 3 days following MI, both fetal and adult hearts demonstrated significant infarcts. At 30 days, the adult heart demonstrated infarct expansion and decreased function. In contrast, the fetal hearts demonstrated resolution of the akinetic myocardium and restoration of cardiac function. However, SDF-1α inhibition transformed the regenerative fetal response into a reparative response similar to the adult. At 30 days, fetal hearts treated with the SDF-1α inhibitor demonstrated a significant increase in infarct size as well as scar formation by histology. In addition, SDF-1α inhibition resulted increased collagen and MMP-9 gene expression.
Conclusion: The fetal regenerative response to myocardial infarction is dependent on the recruitment of cardiac progenitor cells mediated by SDF-1α. These recruited progenitor cells may create an environment conducive to restoration of functional myocardium by altering collagen gene expression and remodeling. These novel findings provide the first evidence that SDF-1α plays a role in the regulation of fibrosis or scar formation. Further studies are need to define the role of progenitor cell recruitment in promoting fetal cardiac regeneration.