Liver sinusoidal endothelial cells (LSECs) critically regulate liver homeostasis and diseases through angiocrine factors. Notch is critical in endothelial cells (ECs). In the current study, Notch signaling was activated by inducible EC‐specific expression of the Notch intracellular domain (NIC). We found that endothelial Notch activation damaged liver homeostasis. Notch activation resulted in decreased fenestration and increased basement membrane, and a gene expression profile with decreased LSEC‐associated genes and increased continuous EC‐associated genes, suggesting LSEC dedifferentiation. Consistently, endothelial Notch activation enhanced hepatic fibrosis (HF) induced by CCl4. Notch activation attenuated endothelial nitric oxide synthase (eNOS)/soluble guanylate cyclase (sGC) signaling, and activation of sGC by 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole (YC‐1) reversed the dedifferentiation phenotype. In addition, Notch activation subverted the hepatocyte‐supporting angiocrine profile of LSECs by down‐regulating critical hepatocyte mitogens, including Wnt2a, Wnt9b, and hepatocyte growth factor (HGF). This led to compromised hepatocyte proliferation under both quiescent and regenerating conditions. Whereas expression of Wnt2a and Wnt9b was dependent on eNOS‐sGC signaling, HGF expression was not rescued by the sGC activator, suggesting heterogeneous mechanisms of LSECs to maintain hepatocyte homeostasis. Conclusion: Endothelial Notch activation results in LSEC dedifferentiation and accelerated liver fibrogenesis through eNOS‐sGC signaling, and alters the angiocrine profile of LSECs to compromise hepatocyte proliferation and liver regeneration (LR). (Hepatology 2018).
Mounting evidence has shown that induction of epithelial-mesenchymal transition (EMT) contributes to the the expression of CSC (cancer stem cell) markers. However, whether and how CSC markers could be involved in regulating EMT has rarely been reported. CD44, being one of the most commonly used CSC markers in hepatocellular carcinoma (HCC), has been demonstrated to act as a multidomain, transmembrane platform that serves to integrate a wide variety of extracellular signals. Therefore, we determined to seek whether CD44 is necessary for the EMT process in HCC. First, we noticed that CD44 expression was associated with the mesenchymal phenotype in HCC cell lines, and knocking down CD44 with lentivirus-mediated shRNA in HCC cell lines resulted in the mesenchymal-epithelial-transition (MET) and the subsequent impaired migration and invasion in vitro. Moreover, in a metastatic mice model established by tail vein injection of luciferase labelled MHCC97-H cells, we confirmed that CD44 knockdown resulted in the decreased metastasis of HCC cells. Furthermore, we found that the induction of MET by CD44 inhibition might be achieved, at least in part, by repressing the ERK/Snail pathway.
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