Sustained IGF-1 secretion by adipose-derived stem cells improves infarcted heart function

Luiza L. Bagno, Deivid Carvalho, Fernanda Mesquita, Ruy A. Louzada, Bruno Andrade, Taís H. Kasai-Brunswick, Vivian M. Lago, Grazielle Suhet, Debora Cipitelli, João Pedro Werneck-de-Castro, Antônio C. Campos-de-Carvalho

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1609-1622
Number of pages14
JournalCell transplantation
Volume25
Issue number9
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • Adipose-derived stem cells (ADSCs)
  • Cell therapy
  • Gene therapy
  • Insulin-like growth factor-1 (IGF-1) overexpression
  • Myocardial infarction

ASJC Scopus subject areas

  • Biomedical Engineering
  • Cell Biology
  • Transplantation

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