Background: We have previously used an injectable collagen matrix (+/- sialyl LewisX (sLeX)), to restore perfusion in ischemic skeletal muscle. This study sought to determine the ability of matrix therapy to support heart regeneration after myocardial infarction (MI).
Methods: MI was induced in C57BL/6J mice by left anterior descending artery ligation. One week post-MI, mice received intramyocardial injections of: 1) PBS; 2) collagen matrix; or 3) sLeX-collagen matrix. Some animals were sacrificed at 1 wk post-treatment for gene and microRNA expression analysis (n≥4). Heart function was assessed by echocardiography and tissues were harvested at 1 month (n≥14).
Results: One week post-treatment, miR-21 and miR-210 (pro-survival microRNAs) expression was greater in hearts treated with sLeX-matrix (by 96% and 40%; p≤0.02) or collagen matrix (by 45% and 33%; p≤0.01), compared to PBS. Also at this time, transcription of cardiac progenitor cell genes was increased in hearts treated with sLeX- matrix (Nkx2.5 (+39%), Sca-1 (+33%) and VEGFR2 (+35%); 0.03≤p≤0.06) or collagen (Nkx2.5 (+52%) and VEGFR2 (+26%); p≤0.05). At 1 month, both matrix treatments improved arteriole density (by ≥80%; p≤0.004), but only sLeX-matrix reduced apoptosis (33% less active caspase-3+ cells; p=0.02). The sLeX-matrix stimulated progenitor cell recruitment and cardiomyogenesis as exhibited by more Nkx2.5+, c-kit+ and connexin43+ cells in the myocardium (by 108%, 33% and 40%, respectively), also accompanied by 60% more proliferating cells (BrdU+), versus PBS (p≤0.05). Furthermore, there were less CD68+ macrophages (by ≥32%) and lower levels of IFNγ and TNFα (by ≥22%) with matrix treatments, suggesting reduced inflammation compared to PBS (p≤0.05). Functionally, compared to baseline (1 wk post-MI), ejection fraction at 1 month was improved with sLeX-matrix treatment (+2.5%), while it was preserved (+0.6%) with collagen matrix, and reduced (-3.6%) with PBS treatment (p≤0.03).
Conclusions: Matrix therapy for MI increased pro-survival microRNA expression and activated host progenitor cells for regeneration. This lead to improved cardiac function with sLeX-matrix, which may be attributed to reduced inflammation and apoptosis, and increased perfusion and cardiomyogenesis.
|Title of host publication||Circulation|
|Publication status||Published - 2012|