title: PSA-NCAM positive neural progenitors stably expressing BDNF promote functional recovery in a mouse model of spinal cord injury.
abstract: BACKGROUND
  Neural stem cells for the treatment of spinal cord injury (SCI) are of particular interest for future therapeutic use. However, until now, stem cell therapies are often limited due to the inhibitory environment following the injury. Therefore, in this study, we aimed at testing a combinatorial approach with BDNF (brain-derived neurotrophic factor) overexpressing early neural progenitors derived from mouse embryonic stem cells. BDNF is a neurotrophin, which both facilitates neural differentiation of stem cells and favors regeneration of damaged axons.
  
  
  METHODS
  Mouse embryonic stem cells, modified to stably express BDNF-GFP, were differentiated into PSA-NCAM positive progenitors, which were enriched, and SSEA1 depleted by a sequential procedure of magnetic-activated and fluorescence-activated cell sorting. Purified cells were injected into the lesion core seven days after contusion injury of the spinal cord in mice, and the Basso mouse scale (BMS) test to evaluate motor function was performed for 5 weeks after transplantation. To analyze axonal regeneration the anterograde tracer biotinylated dextran amine was injected into the sensorimotor cortex two weeks prior to tissue analysis. Cellular differentiation was analyzed by immunohistochemistry of spinal cord sections.
  
  
  RESULTS
  Motor function was significantly improved in animals obtaining transplanted BDNF-GFP-overexpressing cells as compared to GFP-expressing cells and vehicle controls. Stem cell differentiation in vivo revealed an increase of neuronal and oligodendrocytic lineage differentiation by BDNF as evaluated by immunohistochemistry of the neuronal marker MAP2 (microtubule associated protein 2) and the oligodendrocytic markers ASPA (aspartoacylase) and Olig2 (oligodendrocyte transcription factor 2). Furthermore, axonal tracing showed a significant increase of biotin dextran amine positive corticospinal tract fibers in BDNF-GFP-cell transplanted animals caudally to the lesion site.
  
  
  CONCLUSIONS
  The combinatorial therapy approach by transplanting BDNF-overexpressing neural progenitors improved motor function in a mouse contusion model of SCI. Histologically, we observed enhanced neuronal and oligodendrocytic differentiation of progenitors as well as enhanced axonal regeneration.
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany. jwerne01@students.uni-mainz.de.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Butenschön
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany. tina.zimmermann@uni-mainz.de.
authors.forename: Tina
authors.initials: T
authors.lastname: Zimmermann
authors.affiliation: Institute of Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany. nikolai.schmarowski@unimedizin-mainz.de.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Schmarowski
authors.affiliation: Institute of Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany. robert.nitsch@uni-mainz.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany. barbsfa@googlemail.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fackelmeier
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany. kfriedem@uni-mainz.de.|Institute of Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany. kfriedem@uni-mainz.de.|Mouse Behavior Outcome Unit, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University, Hanns-Dieter-Hüsch-Weg 19, 55128, Mainz, Germany. kfriedem@uni-mainz.de.
authors.forename: Kevin
authors.initials: K
authors.lastname: Friedemann
authors.affiliation: Mouse Behavior Outcome Unit, Focus Program Translational Neurosciences (FTN), Johannes Gutenberg University, Hanns-Dieter-Hüsch-Weg 19, 55128, Mainz, Germany. radyushkin@uni-mainz.de.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Radyushkin
authors.affiliation: Institute of Microscopic Anatomy and Neurobiology, University Medical Center, Johannes Gutenberg University, Langenbeckstrasse 1, 55131, Mainz, Germany. jan.baumgart@unimedizin-mainz.de.|Translational Animal Research Center (TARC), University Medical Center, Johannes Gutenberg University, Hanns-Dieter-Hüsch-Weg 19, 55128, Mainz, Germany. jan.baumgart@unimedizin-mainz.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Baumgart
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany. blutz@uni-mainz.de.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, Duesbergweg 6, 55128, Mainz, Germany. leschik@uni-mainz.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Leschik
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology*; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation; D059225:Nociception; D020127:Recovery of Function; D012794:Sialic Acids / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000628:therapy*; D033581:Stem Cell Transplantation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D039842:Neural Cell Adhesion Molecule L1; D012794:Sialic Acids; C103469:polysialyl neural cell adhesion molecule