PMID- 38604156 OWN - NLM STAT- MEDLINE DCOM- 20240423 LR - 20240507 IS - 1945-4589 (Electronic) IS - 1945-4589 (Linking) VI - 16 IP - 7 DP - 2024 Apr 5 TI - TGF-beta downstream of Smad3 and MAPK signaling antagonistically regulate the viability and partial epithelial-mesenchymal transition of liver progenitor cells. PG - 6588-6612 LID - 10.18632/aging.205725 [doi] AB - 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-beta promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-beta activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFbeta-Smad signaling induced growth inhibition and partial EMT, whereas TGFbeta-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-beta was mutually restricted in LPCs. Mechanistically, we found that TGF-beta activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFbeta-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-beta-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-beta-induced cytostasis and partial EMT. CONCLUSION: These results suggested that TGF-beta 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-beta under fibrotic conditions and maintain partial EMT and progenitor phenotypes. FAU - Sun, Yi-Min AU - Sun YM AD - 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. AD - Present address: Department of Gastrointestinal Surgery, Affiliated First Hospital, Yangtze University, Jingzhou, Hubei 434000, China. FAU - Wu, Yu AU - Wu Y AD - 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. FAU - Li, Gan-Xun AU - Li GX AD - 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. FAU - Liang, Hui-Fang AU - Liang HF AD - 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. FAU - Yong, Tu-Ying AU - Yong TY AD - National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430071, China. FAU - Li, Zifu AU - Li Z AD - National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430071, China. FAU - Zhang, Bixiang AU - Zhang B AD - 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. FAU - Chen, Xiao-Ping AU - Chen XP AD - 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. FAU - Jin, Guan-Nan AU - Jin GN AD - 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. AD - Present address: Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. FAU - Ding, Ze-Yang AU - Ding ZY AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20240405 PL - United States TA - Aging (Albany NY) JT - Aging JID - 101508617 RN - 0 (Smad3 Protein) RN - 0 (Transforming Growth Factor beta) SB - IM MH - *Epithelial-Mesenchymal Transition MH - *Smad3 Protein/metabolism MH - *Stem Cells/metabolism MH - Animals MH - *Transforming Growth Factor beta/metabolism MH - *MAP Kinase Signaling System/physiology MH - *Liver/metabolism MH - Cell Survival/drug effects MH - Phosphorylation MH - Mice MH - Signal Transduction PMC - PMC11042936 OTO - NOTNLM OT - MAPK signaling OT - Smad3 OT - TGF-beta OT - liver progenitor cells OT - partial epithelial-mesenchymal transition OT - proliferation COIS- CONFLICTS OF INTEREST: ZD served as a speaker and consultant for Bayer, Eisai, Roche, MSD, AstraZeneca, Innovent, Hengrui, and BeiGene. The remaining authors have nothing to disclose. EDAT- 2024/04/12 00:44 MHDA- 2024/04/23 15:51 PMCR- 2024/04/15 CRDT- 2024/04/11 18:33 PHST- 2023/05/12 00:00 [received] PHST- 2024/03/18 00:00 [accepted] PHST- 2024/04/23 15:51 [medline] PHST- 2024/04/12 00:44 [pubmed] PHST- 2024/04/11 18:33 [entrez] PHST- 2024/04/15 00:00 [pmc-release] AID - 205725 [pii] AID - 10.18632/aging.205725 [doi] PST - ppublish SO - Aging (Albany NY). 2024 Apr 5;16(7):6588-6612. doi: 10.18632/aging.205725. Epub 2024 Apr 5.