Mitotically inactivated embryonic stem cells can be used as an in vivo feeder layer to nurse damaged myocardium after acute myocardial infarction: a preclinical study.
BACKGROUND
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.


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.
Division of Immunotherapy, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. rburt@northwestern.edu
Richard K
RK
Burt
You-hong
YH
Chen
Larissa
L
Verda
Carolina
C
Lucena
Shankararao
S
Navale
Jesse
J
Johnson
Xiaoqiang
X
Han
Jon
J
Lomasney
Jessa M
JM
Baker
Ka-Leung
KL
Ngai
Aya
A
Kino
James
J
Carr
Jan
J
Kajstura
Piero
P
Anversa
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006085:Graft Survival / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*; D059467:Transcriptome; D014183:Transplantation, Heterologous