Abstract
Wnt11 is a key regulator of cardiac muscle cell proliferation and differentiation during heart development. Here, we hypothesized that preprogramming mesenchymal stem cells (MSC) with Wnt11 enhanced angiogenesis in ischemic myocardium. Methods and Results: An acute myocardial infarction model in SD rats was developed by ligation of the left anterior descending (LAD) coronary artery. Rat bone marrow derived MSC were transduced with Wnt11 gene (MSC-Wnt11) and transplanted into ischemic border area. The animals treated with MSC-Wnt11 showed a significantly improved cardiac function. Furthermore, fluorescent microsphere and histological studies revealed an increased blood flow and blood vessel density in MSC-Wnt11 transplanted animals. In vitro studies using conditioned medium (CdM) obtained from MSC-Wnt11 (CdM-Wnt11) showed an increased the length and number of capillary-like structure (CLS) formation and promoted migration of human umbilical vein endothelial cells (HUVECs), which was similar to that HUVECs were directly treated with recombinant Wnt11 proteins. However, these effects could be abolished by using a Wnt11 neutralizing antibody. Real-time PCR analysis indicated that the expression of novel PKCs including PKCδ, PKCε, PKCη, and PKCθ was significantly upregulated in HUVECs transduced with Wnt11 (H-Wnt11). Immunostaining and western blotting results showed that the protein levels of p-pan-PKC and p-JNK as well as VEGFA in H-Wnt11 were significantly higher than that in control HUVECs. However, no difference was detected in the expression of either p-p38 or p-ERK between H-Wnt11 and its control. Furthermore, the enhanced CLS formation and migration of HUVECs mediated by CdM-Wnt11 were partially abolished by using JNK inhibitor, SP600125 (5 μM) and PKC inhibitor, Calphostin-C (0.1 μM). Conclusion: Our results demonstrated, for the first time, that Wnt11 delivered by MSC improved cardiac function and promotes angiogenesis in ischemic myocardium, which may be associated with the activation of the non-canonical Wnt-PKC-JNK pathway.
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