title: Transplantation of human oligodendrocyte progenitor cells in an animal model of diffuse traumatic axonal injury: survival and differentiation.
abstract: BACKGROUND
  Diffuse axonal injury is an extremely common type of traumatic brain injury encountered in motor vehicle crashes, sports injuries, and in combat. Although many cases of diffuse axonal injury result in chronic disability, there are no current treatments for this condition. Its basic lesion, traumatic axonal injury, has been aggressively modeled in primate and rodent animal models. The inexorable axonal and perikaryal degeneration and dysmyelination often encountered in traumatic axonal injury calls for regenerative therapies, including therapies based on stem cells and precursors. Here we explore the proof of concept that treatments based on transplants of human oligodendrocyte progenitor cells can replace or remodel myelin and, eventually, contribute to axonal regeneration in traumatic axonal injury.
  
  
  METHODS
  We derived human oligodendrocyte progenitor cells from the human embryonic stem cell line H9, purified and characterized them. We then transplanted these human oligodendrocyte progenitor cells into the deep sensorimotor cortex next to the corpus callosum of nude rats subjected to traumatic axonal injury based on the impact acceleration model of Marmarou. We explored the time course and spatial distribution of differentiation and structural integration of these cells in rat forebrain.
  
  
  RESULTS
  At the time of transplantation, over 90 % of human oligodendrocyte progenitor cells expressed A2B5, PDGFR, NG2, O4, Olig2 and Sox10, a profile consistent with their progenitor or early oligodendrocyte status. After transplantation, these cells survived well and migrated massively via the corpus callosum in both injured and uninjured brains. Human oligodendrocyte progenitor cells displayed a striking preference for white matter tracts and were contained almost exclusively in the corpus callosum and external capsule, the striatopallidal striae, and cortical layer 6. Over 3 months, human oligodendrocyte progenitor cells progressively matured into myelin basic protein(+) and adenomatous polyposis coli protein(+) oligodendrocytes. The injured environment in the corpus callosum of impact acceleration subjects tended to favor maturation of human oligodendrocyte progenitor cells. Electron microscopy revealed that mature transplant-derived oligodendrocytes ensheathed host axons with spiral wraps intimately associated with myelin sheaths.
  
  
  CONCLUSIONS
  Our findings suggest that, instead of differentiating locally, human oligodendrocyte progenitor cells migrate massively along white matter tracts and differentiate extensively into ensheathing oligodendrocytes. These features make them appealing candidates for cellular therapies of diffuse axonal injury aiming at myelin remodeling and axonal protection or regeneration.
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lxu9@jhmi.edu.
authors.forename: Leyan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. jryu4@jhmi.edu.
authors.forename: Jiwon
authors.initials: J
authors.lastname: Ryu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. hhiel1@jhmi.edu.
authors.forename: Hakim
authors.initials: H
authors.lastname: Hiel
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. amen692@gmail.com.
authors.forename: Adarsh
authors.initials: A
authors.lastname: Menon
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. ayushi1@umbc.edu.
authors.forename: Ayushi
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lizrha@gmail.com.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rha
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vmachai1@jhmi.edu.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Mahairaki
authors.affiliation: Departments of Physical and Medical Rehabilitation, Neurological Surgery, and Anatomy and Neurobiology, Sue and Bill Gross Stem Cell Research Center, Institute for Memory Impairments and Neurological Disorders, University of California at Irvine, Irvine, CA, 92697, USA. cummings@uci.edu.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Cummings
authors.affiliation: Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. koliat@jhmi.edu.|Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. koliat@jhmi.edu.|Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. koliat@jhmi.edu.
authors.forename: Vassilis E
authors.initials: VE
authors.lastname: Koliatsos
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000628:therapy*; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D004195:Disease Models, Animal; D000066449:Human Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008854:Microscopy, Electron; D004676:Myelin Basic Protein / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000648:ultrastructure; D051381:Rats; D011923:Rats, Nude; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D004676:Myelin Basic Protein; D020796:Receptor, Platelet-Derived Growth Factor alpha