Cardiac Progenitor Cell Recruitment Modulates Regulation Of Extracellular Matrix Deposition Following Myocardial Infarction
Maggie M. Hodges, Carlos Zgheib, Junwang Xu, Junyi Hu, Sarah A. Hilton, Lindel C. Dewberry, Kenneth W. Liechty.
The Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Colorado School of Medicine and Anschutz Medical Campus, Aurora, CO, USA.
Background: Fetal hearts possess a regenerative phenotype characterized by regeneration of functional myocardium following myocardial infarction (MI). We have demonstrated that treatment of fetal hearts with an inhibitor of stromal cell derived factor-1a (SDF1i) decreases cardiac progenitor cell (CPC) recruitment and impairs regeneration of functional myocardium. We hypothesize that inhibition of CPC recruitment after MI alters extracellular matrix (ECM) regulation, thereby promoting a fibrotic, adult phenotype in the fetal hearts treated with SDF1i.
Methods: Myocardial infarction (MI) was induced in fetal (n=18) and adult (n=5) sheep via ligation of the LAD. Quantitative PCR was used to evaluate the expression of ECM related genes (TGFB1, TGFB3, collagen 1a1, collagen 3a1, elastin, MMP-9) in adult and fetal hearts. Statistical comparisons were made using Student’s t-test, with p<0.05 considered statistically significant.
Results: Three days following MI, fetal infarcts demonstrate attenuated expression of Col1a1, Col3a1, MMP9, Elastin, TGFB1, and TGFB3 when compared to adult infarcts (p<0.05). Thirty days following MI, gene expression in fetal infarcts returned to baseline, while expression of Col1a1, Col3a1, elastin, MMP-9, TGFB1, and TGFB3 remained significantly elevated in adult infarcts. Following treatment with SDF1i, Col1a1, Col3a1, MMP-9, elastin, and TGFB3 are downregulated in fetal infarcts 3 days after MI. Thirty days after MI, fetal infarcts treated with SDF1ai demonstrated upregulation of Col1a1, elastin, MMP-9, TGFB1, and TGFB3.
Conclusions: Inhibition of CPC recruitment in fetal hearts attenuates early expression of ECM related genes, while upregulating ECM related gene expression 30 days after MI, thereby conveying a fibrotic, adult phenotype to the otherwise regenerative fetal myocardium. These results are the first to suggest that CPC recruitment plays a critical role in the regulation of ECM following MI. Developing therapies targeted at increasing CPC recruitment may reduce the adverse deposition of ECM associated with the progression of heart failure.
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