Mitotically Inactivated Embryonic Stem Cells can be Utilized as an In Vivo Feeder Layer to Nurse Damaged Myocardium Following Acute Myocardial Infarction: A Pre-Clinical Study
Rationale: Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction (AMI). The mechanisms for improvement from different stem cell populations remain unknown.
Objective: To determine if irradiated (non-viable) embryonic stem cells (iESC) improve post ischemic cardiac function without adverse consequences.
Methods and Results: After coronary artery ligation-induced cardiac infarction either conditioned media or male murine or male human iESC were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESC, despite irradiation doses that prevented proliferation and/ or induced cell death, significantly improved cardiac function and decreased infarct size compared to untreated or media treated controls. Fluorescent in situ hybridization (FISH) for the y-chromosome revealed disappearance of iESC within the myocardium, while 5-bromo-2'-deoxyuridine assays revealed de novo in vivo cardiomyocyte DNA synthesis. Microarray gene expression profiling demonstrated an early increase in metabolism, DNA proliferation, and chromatin remodeling pathways, and decrease in fibrosis and inflammatory gene expression compared to media treated controls.
Conclusions: Due to irradiation prior to injection, ex vivo and in vivo iESC existence is transient, yet iESC provide a significant improvement in cardiac function after AMI. The mechanism(s) of action of iESC appears to be related to cell-cell exchange, paracrine factors, and or a scaffolding effect between iESC and neighboring host cardiomyocytes.
- Received December 22, 2011.
- Accepted August 21, 2012.
- Copyright © 2012, American Heart Association