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Modulating myocardial remodeling
Acellular hydrogels have shown promise in improving cardiac function after myocardial infarction in preclinical animal models. Contessotto et al. developed a sheep model of non–ST elevation myocardial infarction, a form of infarction that does not involve the full thickness of the wall of the heart. Treating this sheep model with a degradable elastin-like polypeptide hydrogel, which mimics the extracellular matrix, reduced fibrosis and angiogenesis in the ischemic region, improved cardiac function, and maintained cardiomyocyte integrity in the border zone of infarcts. Results suggest that this hydrogel may help modulate post-ischemic cardiac remodeling.
Abstract
Ischemic heart disease is a leading cause of mortality due to irreversible damage to cardiac muscle. Inspired by the post-ischemic microenvironment, we devised an extracellular matrix (ECM)–mimicking hydrogel using catalyst-free click chemistry covalent bonding between two elastin-like recombinamers (ELRs). The resulting customized hydrogel included functional domains for cell adhesion and protease cleavage sites, sensitive to cleavage by matrix metalloproteases overexpressed after myocardial infarction (MI). The scaffold permitted stromal cell invasion and endothelial cell sprouting in vitro. The incidence of non-transmural infarcts has increased clinically over the past decade, and there is currently no treatment preventing further functional deterioration in the infarcted areas. Here, we have developed a clinically relevant ovine model of non-transmural infarcts induced by multiple suture ligations. Intramyocardial injections of the degradable ELRs-hydrogel led to complete functional recovery of ejection fraction 21 days after the intervention. We observed less fibrosis and more angiogenesis in the ELRs-hydrogel–treated ischemic core region compared to the untreated animals, as validated by the expression, proteomic, glycomic, and histological analyses. These findings were accompanied by enhanced preservation of GATA4+ cardiomyocytes in the border zone of the infarct. We propose that our customized ECM favors cardiomyocyte preservation in the border zone by modulating the ischemic core and a marked functional recovery. The functional benefits obtained by the timely injection of the ELRs-hydrogel in a clinically relevant MI model support the potential utility of this treatment for further clinical translation.
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