title: Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis.
abstract: FTY720 has recently been approved as an oral drug for treating relapsing forms of multiple sclerosis, and exerts its therapeutic effect by acting as an immunological inhibitor targeting the sphingosine-1-phosphate (S1P) receptor subtype (S1P1) of T cells. Recently studies demonstrated positive efficacy of this drug on spinal cord injury (SCI) in animal models after systemic administration, albeit with significant adverse side effects. We hereby hypothesize that localized delivery of FTY720 can promote SCI recovery by reducing pathological astrogliosis. The mechanistic functions of FTY720 were investigated in vitro and in vivo utilizing immunofluorescence, histology, MRI and behavioral analysis. The in vitro study showed that FTY720 can reduce astrocyte migration and proliferation activated by S1P. FTY720 can prolong internalization of S1P1 and exert antagonistic effects on S1P1. In vivo study of SCI animal models demonstrated that local delivery of FTY720 with polycaprolactone (PCL) membrane significantly decreased S1P1 expression and glial scarring compared with the control group. Furthermore, FTY720-treated groups exhibited less cavitation volume and neuron loss, which significantly improved recovery of motor function. These findings demonstrated that localized delivery of FTY720 can promote SCI recovery by targeting the S1P1 receptor of astrocytes, provide a new therapeutic strategy for SCI treatment.
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
authors.forename: Junjuan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; The 2nd Affliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jiaqiu
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: The 1st Affliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Hong
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Biosystems Science & Engineering (D-BSSE), ETH-Zurich, Basel, Switzerland.
authors.forename: Boon Chin
authors.initials: BC
authors.lastname: Heng
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China. Electronic address: zhoujing@zju.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Center for Stem Cell and Tissue Engineering, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Hangzhou, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ouyang
mesh_terms: D000287:Administration, Topical; D000818:Animals; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage*; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008567:Membranes, Artificial; D011091:Polyesters / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D016896:Treatment Outcome
chemical_list: D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D008567:Membranes, Artificial; D011091:Polyesters; C016240:polycaprolactone; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Astrogliosis; Drug release; FTY720; S1P; Spinal cord injury