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Paracrine Engineering of Human Cardiac Stem Cells With Insulin-Like Growth Factor 1 Enhances Myocardial Repair.


ABSTRACT:

Background

Insulin-like growth factor 1 (IGF-1) activates prosurvival pathways and improves postischemic cardiac function, but this key cytokine is not robustly expressed by cultured human cardiac stem cells. We explored the influence of an enhanced IGF-1 paracrine signature on explant-derived cardiac stem cell-mediated cardiac repair.

Methods and results

Receptor profiling demonstrated that IGF-1 receptor expression was increased in the infarct border zones of experimentally infarcted mice by 1 week after myocardial infarction. Human explant-derived cells underwent somatic gene transfer to overexpress human IGF-1 or the green fluorescent protein reporter alone. After culture in hypoxic reduced-serum media, overexpression of IGF-1 enhanced proliferation and expression of prosurvival transcripts and prosurvival proteins and decreased expression of apoptotic markers in both explant-derived cells and cocultured neonatal rat ventricular cardiomyocytes. Transplant of explant-derived cells genetically engineered to overexpress IGF-1 into immunodeficient mice 1 week after infarction boosted IGF-1 content within infarcted tissue and long-term engraftment of transplanted cells while reducing apoptosis and long-term myocardial scarring.

Conclusions

Paracrine engineering of explant-derived cells to overexpress IGF-1 provided a targeted means of improving cardiac stem cell-mediated repair by enhancing the long-term survival of transplanted cells and surrounding myocardium.

SUBMITTER: Jackson R 

PROVIDER: S-EPMC4599498 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Paracrine Engineering of Human Cardiac Stem Cells With Insulin-Like Growth Factor 1 Enhances Myocardial Repair.

Jackson Robyn R   Tilokee Everad L EL   Latham Nicholas N   Mount Seth S   Rafatian Ghazaleh G   Strydhorst Jared J   Ye Bin B   Boodhwani Munir M   Chan Vincent V   Ruel Marc M   Ruddy Terrence D TD   Suuronen Erik J EJ   Stewart Duncan J DJ   Davis Darryl R DR  

Journal of the American Heart Association 20150911 9


<h4>Background</h4>Insulin-like growth factor 1 (IGF-1) activates prosurvival pathways and improves postischemic cardiac function, but this key cytokine is not robustly expressed by cultured human cardiac stem cells. We explored the influence of an enhanced IGF-1 paracrine signature on explant-derived cardiac stem cell-mediated cardiac repair.<h4>Methods and results</h4>Receptor profiling demonstrated that IGF-1 receptor expression was increased in the infarct border zones of experimentally infa  ...[more]

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