TGF-β downstream of Smad3 and MAPK signaling antagonistically regulate the viability and partial epithelial-mesenchymal transition of liver progenitor cells.

Autor:	Sun YM; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.; Present address: Department of Gastrointestinal Surgery, Affiliated First Hospital, Yangtze University, Jingzhou, Hubei 434000, China., Wu Y; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China., Li GX; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China., Liang HF; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China., Yong TY; National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430071, China., Li Z; National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430071, China., Zhang B; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China., Chen XP; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China., Jin GN; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.; Present address: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China., Ding ZY; Hepatic Surgery Center, Hubei Province for The Clinical Medicine Research Center of Hepatic Surgery and Hubei Key Laboratory of Hepatic-Biliary-Pancreatic Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Jazyk:	angličtina
Zdroj:	Aging [Aging (Albany NY)] 2024 Apr 05; Vol. 16 (7), pp. 6588-6612. Date of Electronic Publication: 2024 Apr 05.
DOI:	10.18632/aging.205725
Abstrakt:	Background: Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances. Results: By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-β promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-β activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFβ-Smad signaling induced growth inhibition and partial EMT, whereas TGFβ-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-β was mutually restricted in LPCs. Mechanistically, we found that TGF-β activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFβ-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-β-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-β-induced cytostasis and partial EMT. Conclusion: These results suggested that TGF-β downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-β under fibrotic conditions and maintain partial EMT and progenitor phenotypes.
Databáze:	MEDLINE
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