Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis
The activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are modulated....
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2019-10-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/8/10/1184 |
| _version_ | 1797709318221463552 |
|---|---|
| author | Pei-Wen Wang Tung-Ho Wu Tung-Yi Lin Mu-Hong Chen Chau-Ting Yeh Tai-Long Pan |
| author_facet | Pei-Wen Wang Tung-Ho Wu Tung-Yi Lin Mu-Hong Chen Chau-Ting Yeh Tai-Long Pan |
| author_sort | Pei-Wen Wang |
| collection | DOAJ |
| description | The activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are modulated. However, the vimentin-mediated cytoskeletal cross talk, as well as the signaling transduction, which further coordinates the cellular responses during hepatic fibrogenesis, is poorly understood. In the current study, both messenger RNA (mRNA) and the vimentin protein were significantly increased in a time-dependent manner in the dimethylnitrosamine (DMN)-exposed liver. In particular, vimentin was highly expressed in the activated HSCs. Again, the overexpressed vimentin was observed in the plasma samples derived from patients with hepatic fibrosis/cirrhosis, suggesting that vimentin may be a key factor in regulating the progression of liver fibrosis. Meanwhile, vimentin knockdown suppressed the migratory propensity, provoked morphological changes, and disturbed the focal adhesions in the HSCs due to the breakdown of associated cytoskeletal proteins. Western blotting showed that vimentin deletion inhibited proliferating cell nuclear antigen (PCNA) and arrested the Rho GTPase family, thereby impairing the HSCs’ growth as well as motility. The phosphorylated extracellular-signal regulated kinase (ERK) and AKT signals were also notably reduced in response to the silence of vimentin. Inhibitors of selected signaling pathways suppressed the migration and differentiation of activated HSCs by regulating specific serine phosphorylated sites on vimentin. Taken together, these findings revealed a novel mechanism of vimentin through which various signaling pathways controlled the proliferation, differentiation, and movement of the HSCs via the ERK/AKT and Rho cascades. |
| first_indexed | 2024-03-12T06:34:47Z |
| format | Article |
| id | doaj.art-18479299d622447791b01439d89602cb |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T06:34:47Z |
| publishDate | 2019-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-18479299d622447791b01439d89602cb2023-09-03T01:21:14ZengMDPI AGCells2073-44092019-10-01810118410.3390/cells8101184cells8101184Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic FibrogenesisPei-Wen Wang0Tung-Ho Wu1Tung-Yi Lin2Mu-Hong Chen3Chau-Ting Yeh4Tai-Long Pan5Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40447, TaiwanDivision of Cardiovascular Surgery, Veterans General Hospital, Kaohsiung 81362, TaiwanDepartment of Chinese Medicine, Chang Gung Memorial Hospital, Keelung 20401, TaiwanDepartment of Psychiatry, Taipei Veterans General Hospital, Taipei 11217, TaiwanLiver Research Center, Chang Gung Memorial Hospital, Taoyuan 33375, TaiwanSchool of Traditional Chinese Medicine, Chang Gung University, Taoyuan 33302, TaiwanThe activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are modulated. However, the vimentin-mediated cytoskeletal cross talk, as well as the signaling transduction, which further coordinates the cellular responses during hepatic fibrogenesis, is poorly understood. In the current study, both messenger RNA (mRNA) and the vimentin protein were significantly increased in a time-dependent manner in the dimethylnitrosamine (DMN)-exposed liver. In particular, vimentin was highly expressed in the activated HSCs. Again, the overexpressed vimentin was observed in the plasma samples derived from patients with hepatic fibrosis/cirrhosis, suggesting that vimentin may be a key factor in regulating the progression of liver fibrosis. Meanwhile, vimentin knockdown suppressed the migratory propensity, provoked morphological changes, and disturbed the focal adhesions in the HSCs due to the breakdown of associated cytoskeletal proteins. Western blotting showed that vimentin deletion inhibited proliferating cell nuclear antigen (PCNA) and arrested the Rho GTPase family, thereby impairing the HSCs’ growth as well as motility. The phosphorylated extracellular-signal regulated kinase (ERK) and AKT signals were also notably reduced in response to the silence of vimentin. Inhibitors of selected signaling pathways suppressed the migration and differentiation of activated HSCs by regulating specific serine phosphorylated sites on vimentin. Taken together, these findings revealed a novel mechanism of vimentin through which various signaling pathways controlled the proliferation, differentiation, and movement of the HSCs via the ERK/AKT and Rho cascades.https://www.mdpi.com/2073-4409/8/10/1184hepatic stellate cellshepatic fibrosisvimentinrhoerkakt |
| spellingShingle | Pei-Wen Wang Tung-Ho Wu Tung-Yi Lin Mu-Hong Chen Chau-Ting Yeh Tai-Long Pan Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis Cells hepatic stellate cells hepatic fibrosis vimentin rho erk akt |
| title | Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis |
| title_full | Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis |
| title_fullStr | Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis |
| title_full_unstemmed | Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis |
| title_short | Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis |
| title_sort | characterization of the roles of vimentin in regulating the proliferation and migration of hscs during hepatic fibrogenesis |
| topic | hepatic stellate cells hepatic fibrosis vimentin rho erk akt |
| url | https://www.mdpi.com/2073-4409/8/10/1184 |
| work_keys_str_mv | AT peiwenwang characterizationoftherolesofvimentininregulatingtheproliferationandmigrationofhscsduringhepaticfibrogenesis AT tunghowu characterizationoftherolesofvimentininregulatingtheproliferationandmigrationofhscsduringhepaticfibrogenesis AT tungyilin characterizationoftherolesofvimentininregulatingtheproliferationandmigrationofhscsduringhepaticfibrogenesis AT muhongchen characterizationoftherolesofvimentininregulatingtheproliferationandmigrationofhscsduringhepaticfibrogenesis AT chautingyeh characterizationoftherolesofvimentininregulatingtheproliferationandmigrationofhscsduringhepaticfibrogenesis AT tailongpan characterizationoftherolesofvimentininregulatingtheproliferationandmigrationofhscsduringhepaticfibrogenesis |