title: Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling.
abstract: Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB) function. Here we report that oligodendrocyte precursor cells (OPCs) secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice) exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity.
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America; SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors: Ji Hae
authors: JH
authors: Seo
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors: Takakuni
authors: T
authors: Maki
authors: Department of Anatomy, Osaka Dental University, Osaka, Japan; Department of Regenerative Medicine, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors: Mitsuyo
authors: M
authors: Maeda
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors: Nobukazu
authors: N
authors: Miyamoto
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors: Anna C
authors: AC
authors: Liang
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors: Kazuhide
authors: K
authors: Hayakawa
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors: Loc-Duyen D
authors: LD
authors: Pham
authors: Department of Anatomy, Osaka Dental University, Osaka, Japan.
authors: Fumihiko
authors: F
authors: Suwa
authors: Department of Regenerative Medicine, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors: Akihiko
authors: A
authors: Taguchi
authors: Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Science, Hyogo College of Medicine, Hyogo, Japan.
authors: Tomohiro
authors: T
authors: Matsuyama
authors: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors: Masafumi
authors: M
authors: Ihara
authors: SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Korea.
authors: Kyu-Won
authors: KW
authors: Kim
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors: Eng H
authors: EH
authors: Lo
authors: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
authors: Ken
authors: K
authors: Arai
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D058953:Neural Stem Cells / Q000166:cytology*; D009836:Oligodendroglia / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta