Article

Combining angiogenic gene and stem cell therapies for myocardial infarction

Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
The Journal of Gene Medicine (Impact Factor: 2.47). 09/2009; 11(9):743-53. DOI: 10.1002/jgm.1362
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "Since the preferred sources of stem cells in most clinical trials are autologous, the factors that contribute to changes in MSCs with age require investigation (Yu et al., 2011). MSCs can secrete cytokines that encourage angiogenesis and inhibit apoptosis (Kang et al., 2009; Pons et al., 2009). The protective role of Sirt1 may be a normal function of endothelial cells (Potente et al., 2007; Ota et al., 2008), but to our knowledge its impact in MSCs has not yet studied. "
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    • "In MI, some early preclinical studies have reported significant therapeutic improvements that were associated with stem cell transplantation [3e5] but clinical trials have failed to translate these results into humans [7] [9] [10]. A potential reason for this failure is the very poor retention rate of stem cells transplanted into the ischemic myocardium; in a recent study, only 2% of injected stem cells remained within the injection zone after 7 days [11]. It is possible that this poor retention of transplanted cells may be related to the inflammatory response associated with ischemia/reperfusion (IR) injury [12e15]. "
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    Biomaterials 11/2011; 33(5):1303-14. DOI:10.1016/j.biomaterials.2011.10.019 · 8.31 Impact Factor
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    • "[9] [10] [11] [12] [13] [14] [15] [16] [17] "
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    The Open Cardiovascular Medicine Journal 11/2010; 4:231-9. DOI:10.2174/1874192401004010231
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