TY - JOUR
T1 - Mitotically inactivated embryonic stem cells can be used as an in vivo feeder layer to nurse damaged myocardium after acute myocardial infarction
T2 - A preclinical study
AU - Burt, Richard K.
AU - Chen, You Hong
AU - Verda, Larissa
AU - Lucena, Carolina
AU - Navale, Shankararao
AU - Johnson, Jesse
AU - Han, Xiaoqiang
AU - Lomasney, Jon
AU - Baker, Jessa M.
AU - Ngai, Ka Leung
AU - Kino, Aya
AU - Carr, James
AU - Kajstura, Jan
AU - Anversa, Piero
PY - 2012/10/26
Y1 - 2012/10/26
N2 - RATIONALE: Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown. OBJECTIVE: To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences. METHODS AND RESULTS: After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 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 a decrease in fibrosis and inflammatory gene expression compared with media-treated controls. CONCLUSIONS: As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.
AB - RATIONALE: Various types of viable stem cells have been reported to result in modest improvement in cardiac function after acute myocardial infarction. The mechanisms for improvement from different stem cell populations remain unknown. OBJECTIVE: To determine whether irradiated (nonviable) embryonic stem cells (iESCs) improve postischemic cardiac function without adverse consequences. METHODS AND RESULTS: After coronary artery ligation-induced cardiac infarction, either conditioned media or male murine or male human iESCs were injected into the penumbra of ischemic myocardial tissue of female mice or female rhesus macaque monkeys, respectively. Murine and human iESCs, despite irradiation doses that prevented proliferation and induced cell death, significantly improved cardiac function and decreased infarct size compared with untreated or media-treated controls. Fluorescent in situ hybridization of the Y chromosome revealed disappearance of iESCs within the myocardium, whereas 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 a decrease in fibrosis and inflammatory gene expression compared with media-treated controls. CONCLUSIONS: As a result of irradiation before injection, ex vivo and in vivo iESC existence is transient, yet iESCs provide a significant improvement in cardiac function after acute myocardial infarction. The mechanism(s) of action of iESCs seems to be related to cell-cell exchange, paracrine factors, and a scaffolding effect between iESCs and neighboring host cardiomyocytes.
KW - acute myocardial infarction
KW - embryonic stem cells
KW - irradiated stem cells
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U2 - 10.1161/CIRCRESAHA.111.262584
DO - 10.1161/CIRCRESAHA.111.262584
M3 - Article
C2 - 22914647
SN - 0009-7330
VL - 111
SP - 1286
EP - 1296
JO - Circulation research
JF - Circulation research
IS - 10
ER -