Bibliographic Details
| Title: |
USP9X-enriched MSC-sEV inhibits LSEC angiogenesis in MASH mice by downregulating the IκBα/NF-κB/Ang-2 pathway |
| Authors: |
Yanjin Wang, Chen Wang, Fuji Yang, Yifei Chen, Yujie Shi, Ruizi Xu, Zhuan Zhang, Yongmin Yan |
| Source: |
Pharmacological Research, Vol 209, Iss , Pp 107471- (2024) |
| Publisher Information: |
Elsevier, 2024. |
| Publication Year: |
2024 |
| Collection: |
LCC:Therapeutics. Pharmacology |
| Subject Terms: |
MSC-sEV, USP9X, Ang-2, LSEC, MASH, Therapeutics. Pharmacology, RM1-950 |
| More Details: |
Pathological angiogenesis of liver sinusoidal endothelial cells (LSEC) plays a crucial role in the progression of metabolic dysfunction-associated steatohepatitis (MASH)-induced liver fibrosis. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have shown promising therapeutic potential against MASH. This study aimed to investigate the impact of MSC-sEV on LSEC angiogenesis and elucidate the underlying molecular mechanisms. The effects of MSC-sEV on LSEC angiogenesis were evaluated in Tumor Necrosis Factor- alpha (TNF-α)-treated LSECs in vitro and in Methionine and Choline Deficient Diet (MCD)-induced MASH mice in vivo. Herein, we found that MSC-sEV effectively suppressed LSEC angiogenesis by targeting the angiogenesis marker Angiogenin 2 (Ang-2) in both TNF-α-treated LSECs and MASH mice. Gene manipulation experiments revealed that the primary mechanism by which MSC-sEV inhibited LSEC angiogenesis was through the modulation of nuclear factor kappa B inhibitor alpha (IκBα) / nuclear factor kappa B (NF-κB) / Ang-2 pathway. Additionally, mass spectrometry and co-immunoprecipitation (Co-IP) data suggested that MSC-sEV delivered the ubiquitin specific peptidase 9 X-linked (USP9X) protein to LSECs, leading to enhanced IκBα deubiquitination and NF-κB in activation, ultimately resulting in the inhibition of Ang-2-mediated LSEC angiogenesis. Knockdown of USP9X attenuated the regulatory effects of MSC-sEV on Ang-2 expression, LSEC angiogenesis, and the progression of MASH. In conclusion, our findings indicate that USP9X delivered via MSC-sEV can suppress LSEC angiogenesis and alleviate MASH-induced liver fibrosis through the IκBα/NF-κB/Ang-2 signaling pathway. |
| Document Type: |
article |
| File Description: |
electronic resource |
| Language: |
English |
| ISSN: |
1096-1186 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S104366182400416X; https://doaj.org/toc/1096-1186 |
| DOI: |
10.1016/j.phrs.2024.107471 |
| Access URL: |
https://doaj.org/article/2bdb0191db0e43dbac2502f184fd309a |
| Accession Number: |
edsdoj.2bdb0191db0e43dbac2502f184fd309a |
| Database: |
Directory of Open Access Journals |
