title: Macrophages induce AKT/β-catenin-dependent Lgr5+stem cell activation and hair follicle regeneration through TNF.
abstract: Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen-anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF-induced AKT signalling in epidermal stem cells in vitro. TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5+HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/β-catenin signalling in Lgr5+HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|Tsinghua-Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen 518055, China.|State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, 518055 Shenzhen, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|Shenzhen Peiyuan Biotechnology Company, Shenzhen 518055, China.
authors.forename: Ruiyun
authors.initials: R
authors.lastname: Tian
authors.affiliation: Department of Orthopedics, The General Hospital of Chinese People's Liberation Army, Beijing 100039, China.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Drutskaya
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Chengmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Ge
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Zhimeng
authors.initials: Z
authors.lastname: Fan
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Kong
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Cai
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Jinmei
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.|The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou 510260, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Jia
authors.affiliation: Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou 510260, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: College of Life Sciences, Northeast Forestry University, Harbin 100040, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: Wound Healing Research Group, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada ABT6G2E1.
authors.forename: Edward E
authors.initials: EE
authors.lastname: Tredget
authors.affiliation: The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Lin
authors.affiliation: Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen 518054, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, Graduate School at Shenzhen, Tsinghua University, 518055 Shenzhen, China.
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: The Shenzhen Key Laboratory of Health Sciences and Technology, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, China.|Tsinghua-Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen 518055, China.
authors.forename: Yaojiong
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1 / Q000378:metabolism; D005260:Female; D018859:Hair Follicle / Q000502:physiology*; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012038:Regeneration; D013234:Stem Cells / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; C493597:Lgr5 protein, mouse; C494192:Ly-6C antigen, mouse; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D051057:Proto-Oncogene Proteins c-akt