title: Grafted human embryonic progenitors expressing neurogenin-2 stimulate axonal sprouting and improve motor recovery after severe spinal cord injury.
abstract: BACKGROUND
  Spinal cord injury (SCI) is a widely spread pathology with currently no effective treatment for any symptom. Regenerative medicine through cell transplantation is a very attractive strategy and may be used in different non-exclusive ways to promote functional recovery. We investigated functional and structural outcomes after grafting human embryonic neural progenitors (hENPs) in spinal cord-lesioned rats.
  
  
  RESULTS
  With the objective of translation to clinics we have chosen a paradigm of delayed grafting, i.e., one week after lesion, in a severe model of spinal cord compression in adult rats. hENPs were either naïve or engineered to express Neurogenin 2 (Ngn2). Moreover, we have compared integrating and non-integrating lentiviral vectors, since the latter present reduced risks of insertional mutagenesis. We show that transplantation of hENPs transduced to express Ngn2 fully restore weight support and improve functional motor recovery after severe spinal cord compression at thoracic level. This was correlated with partial restoration of serotonin innervations at lumbar level, and translocation of 5HT1A receptors to the plasma membrane of motoneurons. Since hENPs were not detectable 4 weeks after grafting, transitory expression of Ngn2 appears sufficient to achieve motor recovery and to permit axonal regeneration. Importantly, we also demonstrate that transplantation of naïve hENPs is detrimental to functional recovery.
  
  
  CONCLUSIONS
  Transplantation and short-term survival of Ngn2-expressing hENPs restore weight support after SCI and partially restore serotonin fibers density and 5HT1A receptor pattern caudal to the lesion. Moreover, grafting of naïve-hENPs was found to worsen the outcome versus injured only animals, thus pointing to the possible detrimental effect of stem cell-based therapy per se in SCI. This is of major importance given the increasing number of clinical trials involving cell grafting developed for SCI patients.
authors.affiliation: Neuroscience Department, University of the Basque Country UPV/EHU, IKERBASQUE Basque Foundation for Science, Bilbao, Spain. f.perrin@ikerbasque.org
authors.forename: Florence E
authors.initials: FE
authors.lastname: Perrin
authors.forename: Guillaume
authors.initials: G
authors.lastname: Boniface
authors.forename: Che
authors.initials: C
authors.lastname: Serguera
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lonjon
authors.forename: Angeline
authors.initials: A
authors.lastname: Serre
authors.forename: Monica
authors.initials: M
authors.lastname: Prieto
authors.forename: Jacques
authors.initials: J
authors.lastname: Mallet
authors.forename: Alain
authors.initials: A
authors.lastname: Privat
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D001522:Behavior, Animal; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044968:Regenerative Medicine / Q000379:methods; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000628:therapy*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C491183:NEUROG2 protein, human