title: Encapsulated glucagon-like peptide-1-producing mesenchymal stem cells have a beneficial effect on failing pig hearts.
abstract: Stem cell therapy is an exciting and emerging treatment option to promote post-myocardial infarction (post-MI) healing; however, cell retention and efficacy in the heart remain problematic. Glucagon-like peptide-1 (GLP-1) is an incretin hormone with cardioprotective properties but a short half-life in vivo. The effects of prolonged GLP-1 delivery from stromal cells post-MI were evaluated in a porcine model. Human mesenchymal stem cells immortalized and engineered to produce a GLP-1 fusion protein were encapsulated in alginate (bead-GLP-1 MSC) and delivered to coronary artery branches. Control groups were cell-free beads and beads containing unmodified MSCs (bead-MSC), n = 4-5 per group. Echocardiography confirmed left ventricular (LV) dysfunction at time of delivery in all groups. Four weeks after intervention, only the bead-GLP-1 MSC group demonstrated LV function improvement toward baseline and showed decreased infarction area compared with controls. Histological analysis showed reduced inflammation and a trend toward reduced apoptosis in the infarct zone. Increased collagen but fewer myofibroblasts were observed in infarcts of the bead-GLP-1 MSC and bead-MSC groups, and significantly more vessels per mm(2) were noted in the infarct of the bead-GLP-1 MSC group. No differences were observed in myocyte cross-sectional area between groups. Post-MI delivery of GLP-1 encapsulated genetically modified MSCs provided a prolonged supply of GLP-1 and paracrine stem cell factors, which improved LV function and reduced epicardial infarct size. This was associated with increased angiogenesis and an altered remodeling response. Combined benefits of paracrine stem cell factors and GLP-1 were superior to those of stem cells alone. These results suggest that encapsulated genetically modified MSCs would be beneficial for recovery following MI.
authors.affiliation: Institute for Cardiovascular Science, University of Manchester, Manchester, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Wright
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Farrell
authors.forename: Nadim
authors.initials: N
authors.lastname: Malik
authors.forename: Moustapha
authors.initials: M
authors.lastname: Kassem
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lewis
authors.forename: Christine
authors.initials: C
authors.lastname: Wallrapp
authors.forename: Cathy M
authors.initials: CM
authors.lastname: Holt
mesh_terms: D000464:Alginates / Q000378:metabolism; D019412:Anatomy, Cross-Sectional; D000818:Animals; D017209:Apoptosis; D002316:Cardiotonic Agents / Q000378:metabolism*; D002470:Cell Survival; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D004452:Echocardiography; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D020723:Glucuronic Acid / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006603:Hexuronic Acids / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000628:therapy; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D034421:Sus scrofa; D016277:Ventricular Function, Left
chemical_list: D000464:Alginates; D002316:Cardiotonic Agents; D006603:Hexuronic Acids; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; D020723:Glucuronic Acid