title: Pleiotropic FTY720 Is a Specific and Potent Therapy for Hypertrophic Scars.
abstract: Hypertrophic scarring (HS) is a fibrotic skin condition characterized by aberrant fibroblast phenotypes and excessive deposition of extracellular matrix components. 2-Amino-2-[2-(4-octylphenyl)]-1, 3-propanediol hydrochloride (FTY720), an immunomodulator approved for treating multiple sclerosis, is reported to attenuate fibrosis in multiple disease models. Here we found that FTY720 could significantly attenuate the proliferation and fibrosis in HS fibroblasts (HSFs) and in an animal HS model. Upon treating HSFs or normal dermal fibroblasts with FTY720 at different concentrations for different time periods, we found that FTY720 presented a pleiotropic effect specifically on HSFs but not NFs, including reducing cell viability, arresting cell cycle progression at the G0/G1 phase, promoting apoptosis, inhibiting migration and contraction, and suppressing the expressions of α-smooth muscle actin, collagen I, and collagen III. Mechanistic studies showed that the antifibrotic activities of FTY720 were potentially mediated through sphingosine 1-phosphate receptor 5 to inhibit the protein kinase B/mTOR/p70S6K, but not the Smad, signaling pathway. The in vitro actions of FTY720 also translated into a rabbit ear HS model, stimulating the healing of HS. These findings collectively suggest that FTY720 targets multiple phenotypes of HSFs and is a promising therapeutic agent for HS.
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Canter of Cancer Medicine, Guangzhou, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Department of General Surgery, Shenzhen Seventh People's Hospital, Shenzhen, China.
authors.forename: Da
authors.initials: D
authors.lastname: Ma
authors.affiliation: Department of Plastic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Guo
authors.affiliation: Department of Plastic Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Canter of Cancer Medicine, Guangzhou, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Shanqiang
authors.initials: S
authors.lastname: Qu
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Canter of Cancer Medicine, Guangzhou, China. Electronic address: dengwg@sysucc.org.cn.
authors.forename: Wuguo
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Burn and Plastic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: tangbing@mail.sysu.edu.cn.
authors.forename: Bing
authors.initials: B
authors.lastname: Tang
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D011817:Rabbits; D014945:Wound Healing / Q000187:drug effects*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride