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Nat Commun. 2017 Mar 27;8:14091. doi: 10.1038/ncomms14091.

Macrophages induce AKT/β-catenin-dependent Lgr5+ stem cell activation and hair follicle regeneration through TNF.

Wang X1,2, Chen H2,3,4, Tian R2,5, Zhang Y6, Drutskaya MS7, Wang C1,2, Ge J1,2, Fan Z1,2, Kong D1,2, Wang X1,2, Cai T1,2, Zhou Y1,2, Wang J1,2, Wang J1,2, Wang S1,2, Qin Z8, Jia H9, Wu Y9, Liu J10, Nedospasov SA7, Tredget EE11, Lin M2, Liu J12, Jiang Y4, Wu Y2,3.

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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.
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.
Shenzhen Peiyuan Biotechnology Company, Shenzhen 518055, China.
Department of Orthopedics, The General Hospital of Chinese People's Liberation Army, Beijing 100039, China.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.
Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Guangdong Laboratory Animals Monitoring Institute, Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou 510260, China.
College of Life Sciences, Northeast Forestry University, Harbin 100040, China.
Wound Healing Research Group, Department of Surgery, University of Alberta, Edmonton, Alberta, Canada ABT6G2E1.
Medical Key Laboratory of Health Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, Shenzhen 518054, China.


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.

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