title: Astrocytes Promote Oligodendrogenesis after White Matter Damage via Brain-Derived Neurotrophic Factor.
abstract: Oligodendrocyte precursor cells (OPCs) in the adult brain contribute to white matter homeostasis. After white matter damage, OPCs compensate for oligodendrocyte loss by differentiating into mature oligodendrocytes. However, the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that, during endogenous recovery from white matter ischemic injury, astrocytes support the maturation of OPCs by secreting brain-derived neurotrophic factor (BDNF). For in vitro experiments, cultured primary OPCs and astrocytes were prepared from postnatal day 2 rat cortex. When OPCs were subjected to chemical hypoxic stress by exposing them to sublethal CoCl2 for 7 d, in vitro OPC differentiation into oligodendrocytes was significantly suppressed. Conditioned medium from astrocytes (astro-medium) restored the process of OPC maturation even under the stressed conditions. When astro-medium was filtered with TrkB-Fc to remove BDNF, the BDNF-deficient astro-medium no longer supported OPC maturation. For in vivo experiments, we analyzed a transgenic mouse line (GFAP(cre)/BDNF(wt/fl)) in which BDNF expression is downregulated specifically in GFAP(+) astrocytes. Both wild-type (GFAP(wt)/BDNF(wt/fl) mice) and transgenic mice were subjected to prolonged cerebral hypoperfusion by bilateral common carotid artery stenosis. As expected, compared with wild-type mice, the transgenic mice exhibited a lower number of newly generated oligodendrocytes and larger white matter damage. Together, these findings demonstrate that, during endogenous recovery from white matter damage, astrocytes may promote oligodendrogenesis by secreting BDNF.
  
  
  CONCLUSIONS
  The repair of white matter after brain injury and neurodegeneration remains a tremendous hurdle for a wide spectrum of CNS disorders. One potentially important opportunity may reside in the response of residual oligodendrocyte precursor cells (OPCs). OPCs may serve as a back-up for generating mature oligodendrocytes in damaged white matter. However, the underlying mechanisms are still mostly unknown. Here, we use a combination of cell biology and an animal model to report a new pathway in which astrocyte-derived BDNF supports oligodendrogenesis and regeneration after white matter damage. These findings provide new mechanistic insight into white matter physiology and pathophysiology, which would be broadly and clinically applicable to CNS disease.
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyamoto
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
authors.forename: Akihiro
authors.identifier: http://orcid.org/0000-0001-8029-4958
authors.initials: A
authors.lastname: Shindo
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Liang
authors.affiliation: Multi-Modal Microstructure Analysis Unit, RIKEN CLST-JEOL Collaboration Center, RIKEN Center for Life Science Technologies, Kobe, Japan 650-0047, and.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Maeda
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Egawa
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
authors.forename: Kanako
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and.
authors.forename: Evan K
authors.initials: EK
authors.lastname: Lo
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lok
authors.affiliation: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Suita Osaka, Japan 565-8565.
authors.forename: Masafumi
authors.identifier: http://orcid.org/0000-0002-7102-4048
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, and karai@partners.org.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
mesh_terms: D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002545:Brain Ischemia / Q000150:complications; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D056784:Leukoencephalopathies / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism / Q000473:pathology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology
chemical_list: D016587:Antimutagenic Agents; D019208:Brain-Derived Neurotrophic Factor; D002867:Chromones; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D004676:Myelin Basic Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003035:Cobalt; D051549:Glutathione S-Transferase pi; D010751:Phosphopyruvate Hydratase; C018021:cobaltous chloride
keywords: BDNF; astrocyte; oligodendrogenesis; prolonged cerebral hypoperfusion; white matter injury