title: Repression of TSC1/TSC2 mediated by MeCP2 regulates human embryo lung fibroblast cell differentiation and proliferation.
abstract: Pulmonary fibrosis (PF) is a severe inflammatory disease with limited effective treatments. It is known that the transdifferentiation of human embryo lung fibroblast (HELF) cells from pulmonary fibroblasts into myofibroblasts, contributes to the progression of pulmonary fibrogenesis. The tuberous sclerosis proteins TSC1 and TSC2 are two key signaling factors which can suppress cell growth and proliferation. However, the roles of TSC1 and TSC2 in lung fibroblast are unclear. Here, we developed a PF model with bleomycin (BLM) in mice and conducted several simulation experiments in HELF cells. Our study shows that the expression of TSC1 and TSC2 in fibrotic mice lung was reduced and stimulation of HELF cells with TGF-β1 resulted in a down-regulation of TSC1 and TSC2. In addition, overexpression of TSC1 or TSC2 decreased cell proliferation and differentiation. Furthermore, we found that reduced expression of TSC1 and TSC2 caused by TGF-β1 is associated with the promoter methylation status of TSC1 and TSC2. MeCP2, controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. We found that expression of TSC1 and TSC2 can be repressed by MeCP2, which regulates HELF cell differentiation and proliferation as myofibroblasts and lead to PF ultimately.
authors.affiliation: School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, China; Department of Pharmacology, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei 230601, Anhui, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, China; Hefei Binghu Hospital, 3200 Changsha Road, Hefei 230000, Anhui, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Scientific and Educational, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei 230601, Anhui, China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Deng
authors.affiliation: School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, China.
authors.forename: Erbao
authors.initials: E
authors.lastname: Bian
authors.affiliation: School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei 230601, Anhui, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
authors.affiliation: School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, China.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Lv
authors.affiliation: Department of Pharmacology, The Second Hospital of Anhui Medical University, 678 Furong Road, Hefei 230601, Anhui, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei 230032, Anhui, China. Electronic address: lijun@ahmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000473:pathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D051783:Methyl-CpG-Binding Protein 2; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D053773:Transforming Growth Factor beta1; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
keywords: Human embryonic lung fibroblast cells; TSC1; TSC2