Paracrine Engineering of Human Cardiac Stem Cells to Over-Express Insulin-Like Growth Factor-1 Prevents Cell Death and Enhances Ischemic Myocardial Repair

2013 ◽  
Vol 29 (10) ◽  
pp. S236-S237
Author(s):  
R. Jackson ◽  
E.L. Tilokee ◽  
N. Latham ◽  
B. Ye ◽  
B. Lam ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Growth Factor ◽  
Cardiac Stem Cells ◽  
Insulin Like Growth Factor ◽  
Myocardial Repair

scholarly journals Paracrine Engineering of Human Cardiac Stem Cells With Insulin‐Like Growth Factor 1 Enhances Myocardial Repair

2015 ◽  
Vol 4 (9) ◽  
Author(s):  
Robyn Jackson ◽  
Everad L. Tilokee ◽  
Nicholas Latham ◽  
Seth Mount ◽  
Ghazaleh Rafatian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Cardiac Stem Cells ◽  
Insulin Like Growth Factor ◽  
Myocardial Repair

Abstract 15747: Over-Expression of Insulin-Like Growth Factor-1 by Human Cardiac Stem Cells Enhances Long-Term Retention of Transplanted Cells While Promoting Salvage of Injured Myocardium

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Robyn Jackson ◽  
Everad L Tilokee ◽  
Nicholas Latham ◽  
Bin Ye ◽  
Munir Boodhwani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Annexin V ◽  
Cardiac Repair ◽  
Population Doubling ◽  
Cardiac Stem Cells ◽  
Insulin Like Growth Factor ◽  
Over Expression ◽  
Myocardial Apoptosis

Background: Insulin-like growth factor (IGF-1) is a potent pro-survival cytokine that is not robustly expressed by human cardiac stem cells (CSCs). Previously, we have shown that paracrine engineering of CSCs with IGF-1 improves cell-mediated cardiac repair. Here, we explore the mechanisms underlying IGF-1 enhanced cardiac repair by CSCs. Methods/Results: Sub-culture of isolated c-Kit+, CD90+ and lineage negative cells (c-Kit-/CD90-) demonstrated that the natural low level production of IGF-1 by CSCs (149±16 pg/ml*mg) is secreted by all 3 sub-populations. After culture in hypoxic reduced serum media, lentiviral mediated over-expression of IGF-1 enhanced proliferation (population doubling time: 1.4±1.7 vs.-0.9±1.2 and -1.9±2.4 days, respectively; p≤0.01), expression of pro-survival transcripts (AKT, ERK and MAPK pathways) and pro-survival proteins (Bcl-2, Bcl-x, HIF-1a; p≤0.01) while decreasing expression of apoptotic markers (3.5±0.9 and 3.7±0.9 fold less annexin V; p≤0.01) as compared to GFP- and non-transduced CSCs. The high expression of the IGF-1 (79±3%) or the insulin receptor (61±5%) on CSCs suggests that autocrine pro-survival pre-conditioning underlies these effects. Direct and indirect co-culture of CSCs with neonatal rat ventricular cardiomyocytes (NRVMs) within hypoxic conditions demonstrated that IGF-1 promoted indirect myocardial repair by increasing NRVM viability and pro-survival signaling (Bcl2+; p≤0.01) while reducing apoptosis (annexin V+; p≤0.05) as compared GFP- or non-transduced CSCs. Transplant of CSCs genetically engineered to over-express IGF-1 into immunodeficient mice one week after infarction boosted IGF-1 content within infarcted tissue by 2.9±0.2 fold (p=0.004) and long-term engraftment (+4 weeks human alu content increased by 9.1±4 fold; p=0.05) while reducing myocardial apoptosis (3.4±0.3 and 2.5±0.5 fold reduction expression of Bax and p53, respectively; p<0.05) and long-term myocardial scarring (+ 4 weeks 2.2±0.4 fold less; p=0.01) as compared to GFP-transduced CSCs. Conclusions: Transplantation of IGF-1 enriched CSCs enhances cardiac repair by boosting transplant cell survival and reducing myocardial apoptosis to improve myocardial function and salvage of damaged myocardium.

scholarly journals Insulin-Like Growth Factor-1 Receptor Identifies a Pool of Human Cardiac Stem Cells With Superior Therapeutic Potential for Myocardial Regeneration

2011 ◽  
Vol 108 (12) ◽  
pp. 1467-1481 ◽  
Author(s):  
Domenico D'Amario ◽  
Mauricio C. Cabral-Da-Silva ◽  
Hanqiao Zheng ◽  
Claudia Fiorini ◽  
Polina Goichberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Myocardial Regeneration ◽  
Cardiac Stem Cells ◽  
Insulin Like Growth Factor

scholarly journals Phosphatidylinositol-3,4,5-Trisphosphate Is Required for Insulin-Like Growth Factor 1-Mediated Survival of 3T3-L1 Preadipocytes**This work was supported by a grant (to A.S.) from the Medical Research Council of Canada.

Endocrinology ◽  
2001 ◽  
Vol 142 (1) ◽  
pp. 205-212 ◽  
Author(s):  
AnneMarie Gagnon ◽  
Patti Dods ◽  
Nicolas Roustan-Delatour ◽  
Ching-Shih Chen ◽  
Alexander Sorisky
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Tunel Staining ◽  
Insulin Like Growth Factor ◽  
Tissue Mass ◽  
Akt Phosphorylation ◽  
Dependent Cell ◽  
Phosphoinositide 3 Kinase

Abstract Adipocyte number, a determinant of adipose tissue mass, reflects the balance between the rates of proliferation/differentiation vs. apoptosis of preadipocytes. The percentage of 3T3-L1 preadipocytes undergoing cell death following serum deprivation was reduced by 10 nm insulin-like growth factor (IGF)-1 (from 50.0 ± 0.7% for control starved cells to 27.5 ± 3.1%). TUNEL staining confirmed the apoptotic nature of the cell death. The protective effect of IGF-1 was blocked by phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin, and LY294002, but was unaffected by rapamycin, PD98059, or SB203580, which inhibit mammalian target of rapamycin (mTOR), ERK kinase (MEK1), and p38 MAPK respectively. Exogenous PI(3,4,5)P3 (10 μm), the principal product of IGF-1-stimulated PI3K in 3T3-L1 preadipocytes, had a modest survival effect on its own, reducing cell death from 47.9± 3.4% to 35.6 ± 3.5%. When added to the combination of IGF-1 and LY294002, PI(3,4,5)P3 reversed most of the inhibitory effect of LY294002 on IGF-1-dependent cell survival, protein kinase B/Akt phosphorylation, and caspase-3 activity. Taken together, these results implicate PI(3,4,5)P3 as a necessary signal for the anti-apoptotic action of IGF-1 on 3T3-L1 preadipocytes.

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