Oligodendrocyte precursors induce early blood-brain barrier opening after white matter injury
Ji Hae Seo, … , Eng H. Lo, Ken Arai
Ji Hae Seo, … , Eng H. Lo, Ken Arai
Published January 2, 2013
Citation Information: J Clin Invest. 2013;123(2):782-786. https://doi.org/10.1172/JCI65863.
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Brief Report Neuroscience

Oligodendrocyte precursors induce early blood-brain barrier opening after white matter injury

Abstract

Oligodendrocyte precursor cells (OPCs) are thought to maintain homeostasis and contribute to long-term repair in adult white matter; however, their roles in the acute phase after brain injury remain unclear. Mice that were subjected to prolonged cerebral hypoperfusion stress developed white matter demyelination over time. Prior to demyelination, we detected increased MMP9 expression, blood-brain barrier (BBB) leakage, and neutrophil infiltration in damaged white matter. Notably, at this early stage, OPCs made up the majority of MMP9-expressing cells. The standard MMP inhibitor GM6001 reduced the early BBB leakage and neutrophil infiltration, indicating that OPC-derived MMP9 induced early BBB disruption after white matter injury. Cell-culture experiments confirmed that OPCs secreted MMP9 under pathological conditions, and conditioned medium prepared from the stressed OPCs weakened endothelial barrier tightness in vitro. Our study reveals that OPCs can rapidly respond to white matter injury and produce MMP9 that disrupts the BBB, indicating that OPCs may mediate injury in white matter under disease conditions.

Authors

Ji Hae Seo, Nobukazu Miyamoto, Kazuhide Hayakawa, Loc-Duyen D. Pham, Takakuni Maki, Cenk Ayata, Kyu-Won Kim, Eng H. Lo, Ken Arai

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Figure 2

OPC cultures and in vitro BBB model.

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OPC cultures and in vitro BBB model. (A) Gelatin zymography showed that ...
(A) Gelatin zymography showed that MMP9 but not MMP2 was secreted from cultured rat OPCs by treatment with IL-1β (1-hour treatment at 100 ng/ml followed by 23-hour incubation under normal culture conditions). (B) We prepared conditioned medium from normal OPCs (OPC-CM) or IL-1β–treated OPCs (OPC′-CM), and then added them to cerebral endothelial RBE.4 cells. (C–E) Twenty-four hours after treatment with OPC′-CM degraded the tight-junction protein ZO-1 in RBE.4 cells. n = 3. *P < 0.05. (F and G) Compared with OPC-CM, OPC′-CM increased both endothelial permeability and neutrophil filtration. Importantly, BBB breakdown was reduced by cotreatment with MMP inhibitor GM6001 (10 μM). Ve, vehicle; GM, GM6001. n = 3. *P < 0.05.