title: 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.affiliation: National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
authors.forename: Mahmood S
authors.initials: MS
authors.lastname: Choudhery
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.forename: Ruhma
authors.initials: R
authors.lastname: Mahmood
authors.forename: Sadia
authors.initials: S
authors.lastname: Mohsin
authors.forename: Shoaib
authors.initials: S
authors.lastname: Akhtar
authors.forename: Fatima
authors.initials: F
authors.lastname: Ali
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; C519530:insulin-like growth factor-1, mouse; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose