Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function. Issue 9 (September 2016)

• Record Type: Journal Article
• Authors: Bagno, Luiza L.; Carvalho, Deivid; Mesquita, Fernanda; Louzada, Ruy A.; Andrade, Bruno; Kasai-Brunswick, Taís H.; Lago, Vivian M.; Suhet, Grazielle; Cipitelli, Debora; Werneck-De-Castro, João Pedro; Campos-De-Carvalho, Antonio C.
• Is Part Of: Cell transplantation. Volume 25:Issue 9(2016)
• Page Start: 1609
• Page End: 1622
• Publication Date: 2016-09
• Subjects: Cell therapy -- Gene therapy -- Myocardial infarction -- Adipose-derived stem cells (ADSCs) -- Insulin-like growth factor-1 (IGF-1) overexpression; Cell transplantation -- Periodicals; Cell Transplantation; Cell transplantation; Electronic journals; Periodicals; Periodicals; 571.638
• DOI: 10.3727/096368915X690215
• Languages: English
• ISSNs: 0963-6897

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.