title: Brain-derived neurotrophic factor promotes nerve regeneration by activating the JAK/STAT pathway in Schwann cells.
abstract: BACKGROUND
  Radical prostatectomy (RP) carries the risk of erectile dysfunction (ED) due to cavernous nerve (CN) injury. Schwann cells are essential for the maintenance of integrity and function of peripheral nerves such as the CNs. We hypothesize that brain-derived neurotrophic factor (BDNF) activates the Janus kinase (JAK)/(signal transducer and activator of transcription) STAT pathway in Schwann cells, not in neuronal axonal fibers, with the resultant secretion of cytokines from Schwann cells to facilitate nerve recovery.
  
  
  METHODS
  Using four different cell lines-human neuroblastoma BE(2)-C and SH-SY5Y, human Schwann cell (HSC), and rat Schwann cell (RSC) RT4-D6P2T-we assessed the effect of BDNF application on the activation of the JAK/STAT pathway. We also assessed the time response of JAK/STAT pathway activation in RSCs and HSCs after BDNF treatment. We then assayed cytokine release from HSCs as a response to BDNF treatment using oncostatin M and IL6 as markers.
  
  
  RESULTS
  We showed extensive phosphorylation of STAT3/STAT1 by BDNF at high dose (100 pM) in RSCs, with no JAK/STAT pathway activation in human neuroblastoma cell lines. The time response of JAK/STAT pathway activation in RSCs and HSCs after BDNF treatment showed an initial peak at shortly after treatment and then a second higher peak at 24-48 hours. Cytokine release from HSCs increased progressively after BDNF application, reaching statistical significance for IL6.
  
  
  CONCLUSIONS
  We demonstrated for the first time the indirect mechanism of BDNF enhancement of nerve regeneration through the activation of JAK/STAT pathway in Schwann cells, rather than directly on neurons. As a result of BDNF application, Schwann cells produce cytokines that promote nerve regeneration.
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Guiting
authors.initials: G
authors.lastname: Lin
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Fionna
authors.initials: F
authors.lastname: Sun
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Lu
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Amanda
authors.initials: A
authors.lastname: Reed-Maldonado
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yung-Chin
authors.initials: YC
authors.lastname: Lee
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Guifang
authors.initials: G
authors.lastname: Wang
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Lia
authors.initials: L
authors.lastname: Banie
authors.affiliation: 1 Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA, USA ; 2 Minimally Invasive Urology Center, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250012, China ; 3 Department of Urology, The First Hospital of Jilin University, Changchun 130021, China ; 4 Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tom F
authors.initials: TF
authors.lastname: Lue
keywords: Brain-derived neurotrophic factor (BDNF); Janus kinase/signal transducer and activator of transcription (JAK/STAT); Schwann cells; cavernous nerve injury (CN injury); nerve regeneration