Reversal effect of Jagged1 signaling inhibition on CCl4-induced hepatic fibrosis in rats

Abstract

The role of the Notch ligand Jagged1 in hepatic fibrosis remains to be elucidated. In the current study, we investigated the role of Jagged1 in the activation of hepatic stellate cells (HSCs) and development of hepatic fibrosis in rats. In vitro, Jagged1 in HSCs was downregulated and upregulated by Jagged1 siRNA and pcDNA3.1 Jagged1, respectively. The levels of epithelial-mesenchymal transition (EMT) markers and HSC activation markers were assessed using western blot analysis. The proliferation and migration capacity of HSCs were assessed using 5-ethynyl-2′-deoxyuridine (EdU) incorporation and Transwell migration assays. In vivo, a recombinant adeno-associated virus type 1 (rAAV1) vector carrying Jagged1 shRNA (rAAV1-Jagged1-shRNA) was constructed and transferred to rat livers via the tail vein. Reversion of liver fibrosis and the effect of Jagged1 signaling on EMT were studied using pathological, immunohistochemical and immunofluorescence methods. Our findings revealed that downregulation and upregulation of Jagged1 inhibited and promoted, respectively, HSC activation. The migratory capacity of HSCs was markedly restrained by Jagged1 siRNA. Furthermore, downregulation of Jagged1 suppressed EMT in HSCs. rAAV1-Jagged1-shRNA was generated to treat CCl4-induced hepatic fibrosis in rats. Treatment with rAAV1-Jagged1-shRNA reversed hepatic fibrosis by decreasing EMT. The results of the present study suggest that inhibition of Jagged1 is a potential treatment to ameliorate liver fibrosis.

Blocking development of liver fibrosis augments hepatic progenitor cell‐derived liver regeneration in a mouse chronic liver injury model

“…Our results indicate that both Ac‐HSC‐mediated JAG1‐NOTCH signaling and Ac‐HSC‐produced ECM play a pivotal role in directing HPC differentiation toward BECs, which could suppress the potential for HPCs as a source of HCs. A recent experiment has revealed the direct relationship between JAG1 and HSCs . In this article, the authors confirmed that JAG1 directly acts on the proliferation and epithelial–mesenchymal transition of HSCs in rat liver.…”

“…A recent experiment has revealed the direct relationship between JAG1 and HSCs. 46 In this article, the authors confirmed that JAG1 directly acts on the proliferation and epithelial-mesenchymal transition of HSCs in rat liver. Taken together with our observations, HSC-secreted JAG1 not only modulates HPC differentiation fate, but also acts on activated HSCs in their proliferation and maintenance.…”

The Novel Chinese Medicine JY5 Formula Alleviates Hepatic Fibrosis by Inhibiting the Notch Signaling Pathway

“…TGF-β1 can promote the proliferation and activation of HSC-T25 cells by regulating the Notch signaling pathway ( Aimaiti et al, 2019 ). The Jagged1 gene was successfully knocked down by using rAAV1-Jagged1-shRNA in CCl 4 -induced liver fibrosis, resulting in alleviation of liver fibrosis ( Tang et al, 2017 ). In addition, knockout of the RBP-κB gene, which is considered a key transcription factor in the Notch pathway, can inhibit the proliferation and activation of HSCs to alleviate CCl 4 -induced liver fibrosis in mice ( He et al, 2015 ).…”

JAG1, Regulated by microRNA-424-3p, Involved in Tumorigenesis and Epithelial–Mesenchymal Transition of High Proliferative Potential-Pituitary Adenomas

“…Down-regulation and up-regulation of JAG1 inhibited and promoted, respectively, HSC activation. The migratory capacity of HSCs was markedly restrained by JAG1 siRNA ( 25 ). These reports coincide with our finding that JAG1 mediated adenomas progression by modulating cell proliferation and migration.…”