Microencapsulated Insulin-Like Growth Factor-1 therapy improves cardiac function and reduces fibrosis in a porcine acute myocardial infarction model

Abstract

Insulin-like growth factor-1 (IGF-1) has demonstrated beneficial effects after myocardial infarction (MI). Microencapsulation of IGF-1 could potentially improve results. We aimed to test the effect of an intracoronary (IC) infusion of microencapsulated IGF-1 in a swine acute MI model. For that purpose IC injection of a 10 ml solution of 5 × 10 6 IGF-1 loaded microspheres (MSPs) (n = 8, IGF-1 MSPs), 5 × 10 6 unloaded MSPs (n = 9; MSPs) or saline (n = 7; CON) was performed 48 hours post-MI. Left ventricular ejection fraction (LVEF), indexed ventricular volumes and infarct size (IS) were determined by cardiac magnetic resonance at pre-injection and 10 weeks. Animals were euthanized at 10 weeks, and myocardial fibrosis and vascular density were analysed. End-study LVEF was significantly greater in IGF-1 MSPs compared to MSPs and CON, while ventricular volumes exhibited no significant differences between groups. IS decreased over time in all groups. Collagen volume fraction on the infarct area was significantly reduced in IGF-1 MSPs compared to CON and MSPs. Vascular density analysis of infarct and border zones showed no significant differences between groups. In conclusion, the IC injection of 5 × 10 6 IGF-1 loaded MSPs in a porcine acute MI model successfully improves cardiac function and limits myocardial fibrosis, which could be clinically relevant.Cardiovascular diseases, especially ischemic heart disease, are the leading cause of mortality worldwide accounting for almost 4 million deaths a year in Europe 1,2 . Conventional treatments such as angioplasty and coronary stenting have contributed to reduce early mortality after an acute myocardial infarction (MI) 3 . However, such therapies are only palliative and do not recover the damaged myocardial tissue 4 , so that these diseases still represent a major unmet medical need.In the last two decades stem cell therapy has become a promising treatment option for ischemic cardiomyopathy 5 . As a result, the administration of various cell types has been proposed to address this problem but has shown only moderate improvements in cardiac function 6 .Recently, several studies suggest that the beneficial effect of stem cells does not lie in their multiplication, but in their paracrine actions 7 . Based on this insight, current research directions in regenerative cardiology are moving to a cell-less approach, since it is known now that stem cells are able to secrete combinations of biomolecules that modulate the composition of the damaged cardiac environment contributing to functional tissue repair by stimulating the migration, proliferation and survival of endogenous cardiac progenitor cells (eCSCs) 8,9 , as well as attenuating fibrosis and modulating inflammation 10,11 .Among the secreted substances, there are different cytokines, extracellular vesicles and growth factors including insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF), angiopoietin 2 or vascular endothelial 1

Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction

“…This strategy demonstrated a significant improvement in LVEF correlating with a reduction in myocardial fibrosis. However, no differences either in infarct size or vascular density were found [52]. Finally, intramyocardial treatment of infarcted swine with paMSC engineered to overexpressed IGF-1 and HGF showed a clear reduction in inflammation in some sections analyzed and promoted angiogenic processes in ischemic tissue, although no significant improvements in cardiac function parameters were obtained nor was any relevant synergistic effect found [60].…”

“…Twenty female Large White pigs were subjected to infarct induction as described elsewhere [52]. Briefly, a 7Fr.…”

“…In an MI rat model, IGF-1-adipocyte-derived mesenchymal stem cells improved LV ejection fraction (LVEF) and cardiac contractility index but did not reduce infarct scar size when compared to the control group [51]. Similarly, the administration of microencapsulated IGF-1 in a relevant ischemia-reperfusion MI porcine model improved cardiac function and significantly decreased fibrosis in treated animals compared to controls [52].…”

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model

“…In recent years, heart-derived cells, especially CDCs, have been recognized as an effective cell type for the treatment of ischaemic heart disease [24]. Several preclinical and clinical studies have demonstrated the beneficial effects of these cells in the field of regenerative cardiology [23].…”

Large Animal Models of Cell-Free Cardiac Regeneration

“…In a recent 2020 study, an i.c. injection of microencapsulated insulin like growth factor 1 (IGF-1) was administered 48 h after reperfusion of AMI in a porcine model ( n = 24) [ 64 ]. After 10 weeks of follow-up, the treatment group exhibited significantly higher LVEF (+18%) and vascular density as well as lower collagen volume fraction, indicating decreased fibrosis.…”