Combining angiogenic gene and stem cell therapies for myocardial infarction.
BACKGROUND
Transplantation of stem cells from various sources into infarcted hearts has the potential to promote myocardial regeneration. However, the regenerative capacity is limited partly as a result of the low survival rate of the transplanted cells in the ischemic myocardium. In the present study, we tested the hypothesis that combining cell and angiogenic gene therapies would provide additive therapeutic effects via co-injection of bone marrow-derived mesenchymal stem cells (MSCs) with an adeno-associated viral vector (AAV), MLCVEGF, which expresses vascular endothelial growth factor (VEGF) in a cardiac-specific and hypoxia-inducible manner.


METHODS
MSCs isolated from transgenic mice expressing green fluorescent protein and MLCVEGF packaged in AAV serotype 1 capsid were injected into mouse hearts at the border of ischemic area, immediately after occlusion of the left anterior descending coronary, individually or together. Engrafted cells were detected and quantified by real-time polymerase chain reaction and immunostaining. Angiogenesis and infarct size were analyzed on histological and immunohistochemical stained sections. Cardiac function was analyzed by echocardiography.


RESULTS
We found that co-injection of AAV1-MLCVEGF with MSCs reduced cell loss. Although injection of MSCs and AAV1-MLCVEGF individually improved cardiac function and reduced infarct size, co-injection of MSC and AAV1-MLCVEGF resulted in the best improvement in cardiac function as well as the smallest infarct among all groups. Moreover, injection of AAV1-MLCVEGF induced neovasculatures. Nonetheless, injection of MSCs attracted endogenous stem cell homing and increased scar thickness.


CONCLUSIONS
Co-injection of MLCVEGF and MSCs in ischemic hearts can result in better cardiac function and MSC survival, compared to their individual injections, as a result of the additive effects of each therapy.
Pons
Jennifer
J
Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
Huang
Yu
Y
Takagawa
Junya
J
Arakawa-Hoyt
Janice
J
Ye
Jianqin
J
Grossman
William
W
Kan
Yuet Wai
YW
Su
Hua
H
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation; D002469:Cell Separation; D017931:DNA Primers; D005260:Female; D015316:Genetic Therapy; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000601:surgery / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D033581:Stem Cell Transplantation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D017931:DNA Primers; D042461:Vascular Endothelial Growth Factor A