Manman Ma, Xiaohua Wang, Xiaohui Liu, Yang Han, Yanhui Chu, Yanzhong Guan, Haifeng Liu
{"title":"Engineered fibrotic liver-targeted truncated transforming growth factor β receptor type II variant for superior anti-liver fibrosis therapy","authors":"Manman Ma, Xiaohua Wang, Xiaohui Liu, Yang Han, Yanhui Chu, Yanzhong Guan, Haifeng Liu","doi":"10.1007/s12272-023-01435-4","DOIUrl":null,"url":null,"abstract":"<div><p>Truncated transforming growth factor β receptor type II (tTβRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-β1 by means of competing with wild type TβRII (wtTβRII). However, the widespread application of tTβRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTβRII variant Z-tTβRII by fusing the platelet-derived growth factor β receptor (PDGFβR)-specific affibody Z<sub>PDGFβR</sub> to the N-terminus of tTβRII. The target protein Z-tTβRII was produced using <i>Escherichia coli</i> expression system. In vitro and in vivo studies showed that Z-tTβRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFβR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTβRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-β1/Smad pathway-related protein levels in TGF-β1-stimiluated HSC-T6 cells. Furthermore, Z-tTβRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-β1/Smad signaling pathway in CCl<sub>4</sub>-induced liver fibrotic mice. More importantly, Z-tTβRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTβRII or former variant BiPPB-tTβRII (PDGFβR-binding peptide BiPPB modified tTβRII). In addition, Z-tTβRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTβRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.</p></div>","PeriodicalId":8287,"journal":{"name":"Archives of Pharmacal Research","volume":"46 3","pages":"177 - 191"},"PeriodicalIF":6.9000,"publicationDate":"2023-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Archives of Pharmacal Research","FirstCategoryId":"3","ListUrlMain":"https://link.springer.com/article/10.1007/s12272-023-01435-4","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 2
Abstract
Truncated transforming growth factor β receptor type II (tTβRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-β1 by means of competing with wild type TβRII (wtTβRII). However, the widespread application of tTβRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTβRII variant Z-tTβRII by fusing the platelet-derived growth factor β receptor (PDGFβR)-specific affibody ZPDGFβR to the N-terminus of tTβRII. The target protein Z-tTβRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTβRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFβR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTβRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-β1/Smad pathway-related protein levels in TGF-β1-stimiluated HSC-T6 cells. Furthermore, Z-tTβRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-β1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTβRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTβRII or former variant BiPPB-tTβRII (PDGFβR-binding peptide BiPPB modified tTβRII). In addition, Z-tTβRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTβRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.
期刊介绍:
Archives of Pharmacal Research is the official journal of the Pharmaceutical Society of Korea and has been published since 1976. Archives of Pharmacal Research is an interdisciplinary journal devoted to the publication of original scientific research papers and reviews in the fields of drug discovery, drug development, and drug actions with a view to providing fundamental and novel information on drugs and drug candidates.