Mesenchymal stem cells conditioned with glucose depletion augments their ability to repair-infarcted myocardium.

Abstract

Mesenchymal stem cells (MSCs) are an attractive candidate for autologous cell therapy, but their ability to repair damaged myocardium is severely compromised with advanced age. Development of viable autologous cell therapy for treatment of heart failure in the elderly requires the need to address MSC ageing. In this study, MSCs from young (2 months) and aged (24 months) C57BL/6 mice were characterized for gene expression of IGF-1, FGF-2, VEGF, SIRT-1, AKT, p16(INK4a) , p21 and p53 along with measurements of population doubling (PD), superoxide dismutase (SOD) activity and apoptosis. Aged MSCs displayed senescent features compared with cells isolated from young animals and therefore were pre-conditioned with glucose depletion to enhance age affected function. Pre-conditioning of aged MSCs led to an increase in expression of IGF-1, AKT and SIRT-1 concomitant with enhanced viability, proliferation and delayed senescence. To determine the myocardial repair capability of pre-conditioned aged MSCs, myocardial infarction (MI) was induced in 24 months old C57BL/6 wild type mice and GFP expressing untreated and pre-conditioned aged MSCs were transplanted. Hearts transplanted with pre-conditioned aged MSCs showed increased expression of paracrine factors, such as IGF-1, FGF-2, VEGF and SDF-1α. This was associated with significantly improved cardiac performance as measured by dp/dt(max), dp/dt(min), LVEDP and LVDP, declined left ventricle (LV) fibrosis and apoptosis as measured by Masson's Trichrome and TUNEL assays, respectively, after 30 days of transplantation. In conclusion, pre-conditioning of aged MSCs with glucose depletion can enhance proliferation, delay senescence and restore the ability of aged cells to repair senescent infarcted myocardium.

• Authors: Mahmood S Choudhery, Mohsin Khan, Ruhma Mahmood, Sadia Mohsin, Shoaib Akhtar, Fatima Ali, Shaheen N Khan, Sheikh Riazuddin
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 16 Issue 10 Pg. 2518-29 (Oct 2012) ISSN: 1582-4934 [Electronic] England
• PMID: 22435530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Vascular Endothelial Growth Factor A
• insulin-like growth factor-1, mouse
• vascular endothelial growth factor A, mouse
• Fibroblast Growth Factor 2
• Insulin-Like Growth Factor I
• Superoxide Dismutase
• Proto-Oncogene Proteins c-akt
• Sirt1 protein, mouse
• Sirtuin 1
• Glucose

Topics

• Animals
• Apoptosis
• Cell Proliferation
• Cell Survival
• Cells, Cultured
• Cellular Senescence
• Fibroblast Growth Factor 2 (genetics, metabolism)
• Fibrosis
• Gene Expression Profiling
• Gene Expression Regulation
• Glucose (metabolism)
• Insulin-Like Growth Factor I (genetics, metabolism)
• Kinetics
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (metabolism)
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (physiopathology, therapy)
• Myocardium (pathology)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Signal Transduction
• Sirtuin 1 (genetics, metabolism)
• Superoxide Dismutase (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)