Introduction:
The induction of arteriogenesis is a promising approach for treatment of ischemic cardiomyopathy. Notch signaling has been reported to be a key regulator of arteriogenesis.
Hypothesis:
We hypothesized that Notch-induced human mesenchymal stem cell (SB623) sheet transplantation would induce arteriogenesis in ischemic lesion, leading to improvement of left ventricular function in ischemic cardiomyopathy model rats.
Methods:
Two weeks after the ischemic induction, SB623-patches were transplanted to myocardial infarction model rats (SB group, n=10) or shame operations were performed (Control group, n=10). We evaluated cardiac performance and histology six weeks after the treatment in vivo. In vitro, we performed RNA-sequencing of human umbilical vein endothelial cells (HUVECs) cocultured with SB623s.
Results:
Left ventricular ejection fraction was significantly improved 6 weeks after SB623-sheets transplantation (LVEF, 52±7% vs. 34±5%, p<0.001). Similarly, the attenuation of LV remodeling was observed at 6 weeks (LV diastolic dimension, 73±7 mm vs. 85±5 mm, p<0.001). Histological findings revealed that fibrosis was decreased in SB group (11±1% vs. 22±4%, p=0.02). Furthermore, vWF-positive capillary vessels (vessels, 516±110 /mm
2
vs. 248±26 /mm
2
, p<0.001) and αSMA- and vWF-positive arterioles with over 20μm diameter (arterioles, 25±8 /mm
2
vs. 6±3 /mm
2
, p=0.002) were significantly increased in SB group, suggesting the induction of angiogenesis and arteriogenesis. In vitro, whole transcriptome analysis showed that Notch signaling pathway was significantly upregulated (p<0.001) in HUVECs co-cultured with SB623s. Similarly, pathway analysis revealed upregulated “fluid shear stress and atherosclerosis” pathway (p<0.001) in vitro, suggesting an arteriogenic response of endothelial cell. In vivo study, upregulations of ephrin-B2 (p=0.03) and EphB4 (p=0.01) gene expressions in SB group were confirmed, indicating both arterial and venous remodeling induced by Notch signaling.
Conclusions:
SB623 patch transplantation induces arteriogenesis with functional recovery via Notch signaling in rat myocardial infarction model, proposing a new strategy for the treatment of ischemic cardiomyopathy.