title: Transplantation of adipose-derived stem cells combined with neuregulin-microparticles promotes efficient cardiac repair in a rat myocardial infarction model.
abstract: Tissue engineering is a promising strategy to promote heart regeneration after a myocardial infarction (MI). In this study, we investigated the reparative potential of a system that combines adipose-derived stem cells (ADSCs) with microparticles (MPs) loaded with neuregulin (NRG), named ADSC-NRG-MPs, on a rat MI model. First, cells were attached to the surface of MPs encapsulating NRG and coated with a 1:1 mixture of collagen and poly-d-lysine. One week after in vivo administration, the system favored the shift of macrophage expression from a pro-inflammatory to a regenerative phenotype. At long-term, the adhesion of ADSCs to MPs resulted in an increased cell engraftment, with cells being detectable in the tissue up to three months. In consonance, better tissue repair was observed in the animals treated with cells attached to MPs, which presented thicker left ventricles than the animals treated with ADSCs alone. Moreover, the presence of NRG in the system promoted a more complete regeneration, reducing the infarct size and stimulating cardiomyocyte proliferation. Regarding vasculogenesis, the presence of ADSCs and NRG-MPs alone stimulated vessel formation when compared to the control group, but the combination of both induced the largest vasculogenic effect, promoting the formation of both arterioles and capillaries. Importantly, only when ADSCs were administered adhered to MPs, they were incorporated into newly formed vessels. Collectively, these findings demonstrate that the combination of ADSCs, MPs and NRG favored a synergy for inducing a greater and more complete improvement in heart regeneration and provided strong evidence to move forward with preclinical studies with this strategy.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Díaz-Herráez
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Saludas
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain.
authors.forename: Simón
authors.initials: S
authors.lastname: Pascual-Gil
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Simón-Yarza
authors.affiliation: Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain; Hematology, Cardiology and Cell Therapy, Clínica Universidad de Navarra and Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Abizanda
authors.affiliation: Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain; Hematology, Cardiology and Cell Therapy, Clínica Universidad de Navarra and Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain. Electronic address: egarbayo@unav.es.
authors.forename: Elisa
authors.initials: E
authors.lastname: Garbayo
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain. Electronic address: mjblanco@unav.es.
authors.forename: María José
authors.initials: MJ
authors.lastname: Blanco-Prieto
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002478:Cells, Cultured; D004337:Drug Carriers / Q000737:chemistry*; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D020880:Neuregulins / Q000008:administration & dosage* / Q000627:therapeutic use; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation / Q000379:methods*; D023822:Tissue Engineering / Q000379:methods
chemical_list: D004337:Drug Carriers; D020880:Neuregulins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Cardiac repair; Growth factor; Microparticles; Myocardial infarction; Stem cells; Tissue engineering