title: Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function.
abstract: The mechanism by which stem cell-based therapy improves heart function is still unknown, but paracrine mechanisms seem to be involved. Adipose-derived stem cells (ADSCs) secrete several factors, including insulin-like growth factor-1 (IGF-1), which may contribute to myocardial regeneration. Our aim was to investigate whether the overexpression of IGF-1 in ADSCs (IGF-1-ADSCs) improves treatment of chronically infarcted rat hearts. ADSCs were transduced with a lentiviral vector to induce IGF-1 overexpression. IGF-1-ADSCs transcribe100- to 200-fold more IGF-1 mRNA levels compared to nontransduced ADSCs. IGF-1 transduction did not alter ADSC immunophenotypic characteristics even under hypoxic conditions. However, IGF-1-ADSCs proliferate at higher rates and release greater amounts of growth factors such as IGF-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) under normoxic and hypoxic conditions. Importantly, IGF-1 secreted by IGF-1-ADSCs is functional given that Akt-1 phosphorylation was remarkably induced in neonatal cardiomyocytes cocultured with IGF-1-ADSCs, and this increase was prevented with phosphatidylinositol 3-kinase (PI3K) inhibitor treatment. Next, we tested IGF-1-ADSCs in a rat myocardial infarction (MI) model. MI was performed by coronary ligation, and 4 weeks after MI, animals received intramyocardial injections of either ADSCs (n = 7), IGF-1-ADSCs (n = 7), or vehicle (n = 7) into the infarcted border zone. Left ventricular function was evaluated by echocardiography before and after 6 weeks of treatment, and left ventricular hemodynamics were assessed 7 weeks after cell injection. Notably, IGF-1-ADSCs improved left ventricular ejection fraction and cardiac contractility index, but did not reduce scar size when compared to the ADSC-treated group. In summary, transplantation of ADSCs transduced with IGF-1 is a superior therapeutic approach to treat MI compared to nontransduced ADSCs, suggesting that gene and cell therapy may bring additional benefits to the treatment of MI.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Luiza L
authors.initials: LL
authors.lastname: Bagno
authors.forename: Deivid
authors.initials: D
authors.lastname: Carvalho
authors.forename: Fernanda
authors.initials: F
authors.lastname: Mesquita
authors.forename: Ruy A
authors.initials: RA
authors.lastname: Louzada
authors.forename: Bruno
authors.initials: B
authors.lastname: Andrade
authors.forename: Taís H
authors.initials: TH
authors.lastname: Kasai-Brunswick
authors.forename: Vivian M
authors.initials: VM
authors.lastname: Lago
authors.forename: Grazielle
authors.initials: G
authors.lastname: Suhet
authors.forename: Debora
authors.initials: D
authors.lastname: Cipitelli
authors.forename: João Pedro
authors.initials: JP
authors.lastname: Werneck-de-Castro
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Campos-de-Carvalho
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D033581:Stem Cell Transplantation / Q000379:methods*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I