title: Feasibility of intracoronary GLP-1 eluting CellBead™ infusion in acute myocardial infarction.
abstract: Cell therapy is a field of growing interest in the prevention of post acute myocardial infarction (AMI) heart failure. Stem cell retention upon local delivery to the heart, however, is still unsatisfactory. CellBeads were recently developed as a potential solution to this problem. CellBeads are 170-μm alginate microspheres that contain mesenchymal stem cells (MSCs) genetically modified to express glucagon-like peptide-1 (GLP-1) supplementary to inherent paracrine factors. GLP-1 is an incretin hormone that has both antiapoptotic and cardioprotective effects. Transplanting CellBeads in the post-AMI heart might induce cardiomyocyte salvage and ultimately abrogate adverse cardiac remodeling. We aimed to investigate the feasibility of intracoronary infusion of CellBeads in a large animal model of AMI. Four pigs were used in a pilot study to assess the maximal safe dose of CellBeads. In the remaining 21 animals, an AMI was induced by balloon occlusion of the left circumflex coronary artery for 90 min. During reperfusion, 60,000 CellBeads (n = 11), control beads (n = 4), or lactated Ringers' (n = 6) were infused. Animals were sacrificed after 2 or 7 days, and the hearts were excised for histological analyses. Intracoronary infusion did not permanently affect coronary flow in any of the groups. Histological analysis revealed CellBeads containing viable MSCs up to 7 days. Viability and activity of the MSCs was confirmed by qPCR analysis that showed expression of recombinant GLP-1 and human genes after 2 and 7 days. CellBeads reduced inflammatory infiltration by 29% (p = 0.001). In addition, they decreased the extent of apoptosis by 25% (p = 0.001) after 2 days. We show that intracoronary infusion of 5 million encapsulated MSCs is safe and feasible. Also, several parameters indicate that the cells have paracrine effects, suggesting a potential therapeutic benefit of this new approach.
authors.affiliation: Molecular Cardiology Laboratory, Thoraxcenter, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jaco H
authors.initials: JH
authors.lastname: Houtgraaf
authors.forename: Renate
authors.initials: R
authors.lastname: de Jong
authors.forename: Kim
authors.initials: K
authors.lastname: Monkhorst
authors.forename: Dennie
authors.initials: D
authors.lastname: Tempel
authors.forename: Esther
authors.initials: E
authors.lastname: van de Kamp
authors.forename: Wijnand K
authors.initials: WK
authors.lastname: den Dekker
authors.forename: Kushan
authors.initials: K
authors.lastname: Kazemi
authors.forename: Imo
authors.initials: I
authors.lastname: Hoefer
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lewis
authors.forename: Peter W
authors.initials: PW
authors.lastname: Stratford
authors.forename: Christine
authors.initials: C
authors.lastname: Wallrapp
authors.forename: Felix
authors.initials: F
authors.lastname: Zijlstra
authors.forename: Henricus J
authors.initials: HJ
authors.lastname: Duckers
mesh_terms: D000208:Acute Disease; D000464:Alginates / Q000737:chemistry; D000818:Animals; D017209:Apoptosis; D021721:Balloon Occlusion; D064987:Cell- and Tissue-Based Therapy; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000378:metabolism*; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology; D010865:Pilot Projects; D013552:Swine
chemical_list: D000464:Alginates; D006603:Hexuronic Acids; D052216:Glucagon-Like Peptide 1; D020723:Glucuronic Acid