mTOR Overactivation in Mesenchymal cells Aggravates CCl4− Induced liver Fibrosis
| Autor: | Xiaoying Dong, Wenqing Nai, Chunhong Jia, Meng Dai, Yan Ding, Lanlan Shan, Hongyuan Wu, You Fu, Xiaochun Bai, Wanfu Xu, Ling Zhou, Hang Zheng, Shunzhi Chen |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Liver injury congenital hereditary and neonatal diseases and abnormalities Multidisciplinary Mesenchymal stem cell Biology medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Perisinusoidal space Apoptosis 030220 oncology & carcinogenesis Conditional gene knockout Cancer research medicine Hepatic stellate cell Myofibroblast PI3K/AKT/mTOR pathway |
| Zdroj: | Scientific Reports. 6 |
| ISSN: | 2045-2322 |
| Popis: | Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells. TSC1 CKO and WT mice were subjected to CCl4, oil or CCl4+ rapamycin treatment for 8 weeks. TSC1 CKO mice developed pronounced liver fibrosis relative to WT mice, as examined by ALT, hydroxyproline, histopathology, and profibrogenic gene. Absence of TSC1 in mesenchymal cells induced proliferation and prevented apoptosis in activated HSCs. However, there were no significant differences in oil-treated TSC1 CKO and WT mice. Rapamycin, restored these phenotypic changes by preventing myofibroblasts proliferation and enhancing their apoptosis. These findings revealed mTOR overactivation in mesenchymal cells aggravates CCl4− induced liver fibrosis and the rapamycin prevent its occurance. |
| Databáze: | OpenAIRE |
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