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Cathy M Holt

Cathy M Holt

University of Manchester, UK

Title: Translational models of cardiovascular disease: What have we learnt?

Biography

Cathy M Holt was awarded her PhD at the University of Sheffield where she was subsequently appointed as Lecturer. She then moved to University of Manchester where she leads a research team investigating the causes and prevention of vascular occlusion and stem cell approaches for the treatment of myocardial infarction. She currently serves on the British Atherosclerosis Society committee. She is on the Editorial Board of the journal "Clinical Science" and is Section Head for the Cardiovascular Physiology/Circulation Section in Faculty of 1000. In addition she has a teaching role and was recently awarded Senior Fellowship from the Higher Education Academy.

Abstract

Human mesenchymal stem cells (MSCs) engineered to secrete a Glucagon-like peptide-1 (GLP-1) fusion protein and encapsulated in alginate (GLP-1 Cell-Beads) were developed as a novel therapy for myocardial regeneration post infarction. The effect of this therapy was assessed in an in vivo pig model of myocardial infarction and an in vitro human model of cardiomyocyte ischemia. GLP-1 Cell-Beads were delivered to the left anterior descending coronary artery branches in pigs, creating micro-infarcts. Cell-free beads (empty) and Cell-Beads containing MSCs without GLP-1 (Beads-MSC) were delivered as controls. Echocardiography was used to measure left ventricular function and infarct size was measured macroscopically. Tissue was analyzed for: Inflammation, apoptosis, collagen content and myofibroblast number. Atomic force microscopy (AFM) was used to examine the ultra-structure of the collagen scar. To examine direct effects on apoptosis, human adult cardiomyocytes underwent ischemia followed by incubation with MSC conditioned media echocardiography confirmed MI in all experimental groups of pigs. Four weeks post-MI, treatment with GLP-1 Cell-Beads significantly improved LVEF and limited infarct expansion. Beads-MSCs increased inflammation, which was reduced by GLP-1. Collagen content was increased in the infarct of Bead-MSC and Beads GLP-1 MSC groups compared to the empty bead group, which was associated with a decreased number of myofibroblasts and alterations in the collagen fiber structure. No differences in apoptosis were observed between groups in the in vivo model, however, significantly fewer TUNEL+ cells were observed in human cardiomyocytes in vitro. In conclusion, GLP-1 Cell-Beads have a beneficial effect on healing following MI. The effects are due to a combination of both the GLP-1 and paracrine factors released from the MSCs. These findings require further validation prior to clinical translation.