title: Suppression of MicroRNA-383 Enhances Therapeutic Potential of Human Bone-Marrow-Derived Mesenchymal Stem Cells in Treating Spinal Cord Injury via GDNF.
abstract: OBJECTIVE
  Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) has been used to treat spinal cord injury (SCI) to enhance tissue repair and neural cell regeneration. Glial cell line derived neurotrophic factor (GDNF) is an identified neural growth and survival factor. Here, we examined whether modification of GDNF levels in MSCs may further increase the potential of MSCs in promoting neural cell regeneration and subsequently the therapeutic outcome.
  
  
  METHODS
  We examined the mRNA and protein levels of GDNF in human MSCs by RT-qPCR and Western blot, respectively. Bioinformatics analyses were done to predict microRNAs (miRNAs) that target GDNF in MSCs. The functional binding of miRNAs to GDNF mRNA was examined by a dual luciferase reporter assay. MSCs were transduced with adeno-associated virus (AAV) carrying null or antisense for miR-383 (as-miR-383), which were transplanted into nude rats that underwent SCI. The intact tissue, cavity volume, and recovery of locomotor activity were assessed.
  
  
  RESULTS
  MSCs expressed very low GDNF protein, but surprisingly high levels of GDNF mRNA. Bioinformatics analyses showed that miR-383 inhibited protein translation of GDNF, through binding to the 3'-UTR of the GDNF mRNA. MSCs transduced with AAV-as-miR-383 further increased the intact tissue percentage, decreased cavity volume, and enhanced the recovery of locomotor activity in nude rats that underwent SCI, compared to MSCs.
  
  
  CONCLUSIONS
  Suppression of miR-383 may increase the therapeutic potential of human bone-marrow-derived MSCs in treating SCI via augmentation of GDNF protein levels.
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Guo-Jun
authors.initials: GJ
authors.lastname: Wei
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Gang
authors.initials: G
authors.lastname: An
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Zuo-Wei
authors.initials: ZW
authors.lastname: Shi
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Kai-Fu
authors.initials: KF
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yan-Song
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: En-Ming
authors.initials: EM
authors.lastname: Yu
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, the 1st Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Da-Ming
authors.initials: DM
authors.lastname: Dong
authors.affiliation: Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, The People's Hospital of Yuxi City, The 6th Affiliated Hospital of Kunming Medical University, Yuxi, China.
authors.forename: Zhao-Wei
authors.initials: ZW
authors.lastname: Teng
authors.affiliation: Department of Orthopedics, the Fifth Hospital of Harbin, Harbin, China.
authors.forename: De-Lai
authors.initials: DL
authors.lastname: Zhao
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis*; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000096:biosynthesis*; D051381:Rats; D011923:Rats, Nude; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000628:therapy
chemical_list: D020413:3' Untranslated Regions; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; C558685:MIRN383 microRNA, human; D035683:MicroRNAs
keywords: Glial cell line derived neurotrophic factor (GDNF); Mesenchymal stem cells (MSCs); Spinal cord injury (SCI); miR-383