Elastin-like recombinamers-based hydrogel modulates the post-ischemic remodelling in a clinically-relevant model of myocardial infarction

Abstract

Myocardial infarction (MI) belongs to the family of cardiovascular diseases and represents the primary cause of worldwide mortality. Despite the promising results achieved in both small and large animal studies, recent meta-analyses highlighted the marginal effect of therapeutic strategies like bone-marrow derived stem cells once they are tested in the clinical trials. Mammalian adult cardiomyocytes are able to re-enter the cell-cycle only during the first week after birth, thus avoiding the maladaptive remodelling which characterises post-ischemic phases in the adult. In this thesis a study included the identification of significant differences in the cellular membrane glycosylation from tissue samples harvested from neonatal and adult rats. Increasing evidence has shown the crucial role that components of the extracellular matrix (ECM) can play to modulate the post-ischemic remodelling. Elastin is a natural component of the cardiac ECM and can be mimicked by genetic engineering through the production of elastin-like recombinamers (ELRs). In this thesis, two ELRs named HE5 and HRGD which contain matrix metalloproteinase-responsive and cell-adhesive sequences, respectively, were used to fabricate an acellular hydrogel. This hydrogel, lacking growth factor bioactivity, was applied in this MI model by multiple intramyocardial injections at seven days post-MI and its effects evaluated after 21 days. The ischemic core in the ELRs-treated group showed reduced fibrosis and enhanced angiogenesis. Complete functional recovery in the ejection fraction 21 days after the ELRs-hydrogel injections distinguished this group from the stable impaired behaviour in untreated animals. High-throughput analyses at expression, protein and glycan level were performed, and an enhanced preservation of GATA4+ cardiomyocytes in the border zone of the infarct was observed. The combined effect of a modulated extracellular matrix in the ischemic core and preserved cardiomyocytes in the border zone are likely to be responsible for the marked functional recovery.