title: Adrenomedullin promotes differentiation of oligodendrocyte precursor cells into myelin-basic-protein expressing oligodendrocytes under pathological conditions in vitro.
abstract: Oligodendrocytes, which are the main cell type in cerebral white matter, are generated from their precursor cells (oligodendrocyte precursor cells: OPCs). However, the differentiation from OPCs to oligodendrocytes is disturbed under stressed conditions. Therefore, drugs that can improve oligodendrocyte regeneration may be effective for white matter-related diseases. Here we show that a vasoactive peptide adrenomedullin (AM) promotes the in vitro differentiation of OPCs under pathological conditions. Primary OPCs were prepared from neonatal rat brains, and differentiated into myelin-basic-protein expressing oligodendrocytes over time. This in vitro OPC differentiation was inhibited by prolonged chemical hypoxic stress induced by non-lethal CoCl(2) treatment. However, AM promoted the OPC differentiation under the hypoxic stress conditions, and the AM receptor antagonist AM(22-52) canceled the AM-induced OPC differentiation. In addition, AM treatment increased the phosphorylation level of Akt in OPC cultures, and correspondingly, the PI3K/Akt inhibitor LY294002 blocked the AM-induced OPC differentiation. Taken together, AM treatment rescued OPC maturation under pathological conditions via an AM-receptor-PI3K/Akt pathway. Oligodendrocytes play critical roles in white matter by forming myelin sheath. Therefore, AM signaling may be a promising therapeutic target to boost oligodendrocyte regeneration in CNS disorders.
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, MA General Hospital, Harvard Medical School, USA.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, MA General Hospital, Harvard Medical School, USA; Department of Developmental Neuroscience, United Centers for Advanced Research and Translational Medicine, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, MA General Hospital, Harvard Medical School, USA.
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Miyamoto
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, MA General Hospital, Harvard Medical School, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Liang
authors.affiliation: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, MA General Hospital, Harvard Medical School, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, MA General Hospital, Harvard Medical School, USA. Electronic address: karai@partners.org.
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
mesh_terms: D053607:Adrenomedullin / Q000494:pharmacology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004676:Myelin Basic Protein / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D058265:Receptors, Adrenomedullin / Q000378:metabolism
chemical_list: D004676:Myelin Basic Protein; D010446:Peptide Fragments; D058265:Receptors, Adrenomedullin; C104782:adrenomedullin (22-52); D053607:Adrenomedullin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt