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PLoS One. 2014 Jul 31;9(7):e103174. doi: 10.1371/journal.pone.0103174. eCollection 2014.

Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling.

Author information

1
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.
2
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, United States of America.
3
Department of Anatomy, Osaka Dental University, Osaka, Japan; Department of Regenerative Medicine, Institute of Biomedical Research and Innovation, Kobe, Japan.
4
Department of Anatomy, Osaka Dental University, Osaka, Japan.
5
Department of Regenerative Medicine, Institute of Biomedical Research and Innovation, Kobe, Japan.
6
Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Science, Hyogo College of Medicine, Hyogo, Japan.
7
Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Osaka, Japan.
8
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.

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.

PMID:
25078775
PMCID:
PMC4117639
DOI:
10.1371/journal.pone.0103174
[Indexed for MEDLINE]
Free PMC Article

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