title: Granulocyte-colony stimulating factor promotes brain repair following traumatic brain injury by recruitment of microglia and increasing neurotrophic factor expression.
abstract: The overall objective was to elucidate cellular mechanisms by which G-CSF enhances recovery from traumatic brain injury in a hippocampal-dependent learning task.
  
  
  
  Chimeric mice were prepared by transplanting bone marrow cells that express green fluorescent protein (GFP+) from a transgenic "green" mice into C57BL/6 mice. Two months later, the animals sustained mild controlled cortical impact (CCI) to the right frontal-parietal cortex, followed by G-CSF (100 μg/kg) treatment for 3 consecutive days. The primary behavioral end-point was performance on the radial arm water maze (RAWM) assessed before and after CCI (days 7 and 14). Secondary endpoints included a), motor performance on a rotating cylinder (rotarod), b) measurement of microglial and astroglial response, c) hippocampal neurogenesis, and d) measures of neurotrophic factors (BDNF, GDNF) in brain homogenates.
  
  
  
  G-CSF treatment resulted in significantly better performance on the rotorod at one week, and in the RAWM after one and two weeks. The cellular changes found 2 wks after CCI in the G-CSF group included increased numbers of hippocampal newborn neurons as well as astrocytosis and microgliosis in striatum and frontal cortex on both sides of brain. GFP+ cells that co-labeled with Iba1 (microglial marker) comprised a significant proportion of striatal microglia in G-CSF treated animals, indicating the capacity of G-CSF to increase microglial recruitment to the site of injury. Neurotrophic factors GDNF and BDNF, elaborated by activated microglia and astrocytes, were increased in G-CSF treated mice.
  
  
  
  G-CSF serves as a neurotrophic factor that increases hippocampal neurogenesis (or enhances survival of new-born neurons), and activates astrocytes and microglia. In turn, these activated glia release a plethora of cytokines and neurotrophic factors that contribute, in a poorly understood cascade, to the brain's repair response. G-CSF also acts directly on bone marrow-derived cells to enhance recruitment of microglia to the site of CCI from circulating monocytes to the site of CCI.
authors.affiliation: James A Haley VAH Research Service, Tampa FL, USA.|Department of Neurology, University of South Florida, Tampa, FL, USA.
authors.forename: Shijie
authors.initials: S
authors.lastname: Song
authors.affiliation: James A Haley VAH Research Service, Tampa FL, USA.|Department of Neurosurgery, University of South Florida, Tampa, FL, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Neurosurgery, University of South Florida, Tampa, FL, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Acosta
authors.affiliation: James A Haley VAH Research Service, Tampa FL, USA.|Department of Neurology, University of South Florida, Tampa, FL, USA.
authors.forename: Vasyl
authors.initials: V
authors.lastname: Sava
authors.affiliation: Department of Neurosurgery, University of South Florida, Tampa, FL, USA.
authors.forename: Cesar
authors.initials: C
authors.lastname: Borlongan
authors.affiliation: James A Haley VAH Research Service, Tampa FL, USA.|Department of Neurology, University of South Florida, Tampa, FL, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Sanchez-Ramos
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000601:surgery; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology* / Q000627:therapeutic use*; D006624:Hippocampus / Q000473:pathology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D009479:Neuropeptides / Q000378:metabolism; D004856:Postural Balance; D011597:Psychomotor Performance; D020127:Recovery of Function / Q000502:physiology*
chemical_list: C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009414:Nerve Growth Factors; D009479:Neuropeptides; D016179:Granulocyte Colony-Stimulating Factor
keywords: Granulocyte-colony stimulating factor; astrocytosis; chimeric mice; doublecortin; green fluorescent protein; microgliosis; neuro-inflammation; neurogenesis; traumatic brain injury