Abstract
Background: We demonstrated that the transduction of Wnt11 into mesenchymal stem cells (MSCs) (MSCWnt11) promotes these cells differentiation into cardiac phenotypes. In the present study, we investigated the paracrine effects of MSCWnt11 on cardiac function and angiogenesis. Methods and Results: Conditioned medium was collected from MSCWnt11 (CdMWnt11) and their control cells (CdMGFP). CdMWnt11, especially obtained from MSCWnt11 exposed to hypoxia, significantly promoted human umbilical vein endothelial cells (HUVECs) migration and increased capillary-like tube (CLT) formation, which was blocked by Wnt11 neutralizing antibody. Wnt11 protein was significantly higher in CdMWnt11 compared to that in CdMGFP. Directly treating HUVECs with recombinant Wnt11 protein significantly increased CLT formation, which was abrogated by treating cells with the JNK inhibitor SP600125, as well as the PKC inhibitor Calphostin-C. Moreover, the transfection of Wnt11 to HUVECs (HWnt11) significantly increased CLT formation and HUVEC migration, as well as upregulated p-pan-PKC and p-JNK expression. Injection of CdMWnt11 into the peri-infarct region in a rat acute myocardial infarction (AMI) model significantly improved cardiac function, reduced infarct size, and increased myocardial blood flow and blood vessel density in the ischemic area. Conclusion: Wnt11 released from MSCWnt11 increased angiogenesis and improved cardiac function via non-canonical Wnt-PKC-JNK dependent pathways.
Highlights
Heart failure due to myocardial infarction (MI) is a major cause of morbidity and mortality worldwide, as adult mammalian heart tissue has a limited capability for self-repair
The scale bars represent 50 μm. (B): real-time PCR (RT-PCR) showed that the mRNA of Wnt11 is in MSCWnt11 . (C): Western blot showed the relative expression of Wnt11 normalized to Glycer-aldehyde-3-phosphate dehydrogenase (GAPDH) in significantly increased in MSCWnt11. (C): Western blot showed the relative expression of Wnt11 each sample and compared with the levels in MSCGFP . *, p < 0.05 vs. MSCGFP
Our studies demonstrated that conditioned medium collected from mesenchymal stem cells (MSCs) transduced with Wnt11 (CdMWnt11 ) stimulated endothelial cells to generate capillary-like tube (CLT) and promoted endothelial cell migration
Summary
Heart failure due to myocardial infarction (MI) is a major cause of morbidity and mortality worldwide, as adult mammalian heart tissue has a limited capability for self-repair. Genes 2020, 11, 1277 therapeutics have been shown to improve cardiac function and attenuate infarct size expansion in both experimental and pre-clinical trials [1,2,3,4]. Combining stem cell transplantation with therapeutic gene delivery via genetic modulation of donor cells holds promise for the treatment of ischemic cardiovascular disease [5,8,10]. Wnt signaling regulates a variety of cellular activities, including cell survival, proliferation, migration, and gene expression [11,12,13,14,15,16]. We demonstrated that the transduction of Wnt into mesenchymal stem cells (MSCs) (MSCWnt11 ) promotes these cells differentiation into cardiac phenotypes.
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