Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity

Yao Yao; Zu Lin Chen; Erin H. Norris; Sidney Strickland

doi:10.1038/ncomms4413

Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity

Yao Yao, Zu Lin Chen, Erin H. Norris, Sidney Strickland

Pharmacy Practice and Pharmaceutical Sciences

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244 Scopus citations

Abstract

Blood brain barrier (BBB) breakdown is not only a consequence of but also contributes to many neurological disorders, including stroke and Alzheimer's disease. How the basement membrane (BM) contributes to the normal functioning of the BBB remains elusive. Here we use conditional knockout mice and an acute adenovirus-mediated knockdown model to show that lack of astrocytic laminin, a brain-specific BM component, induces BBB breakdown. Using functional blocking antibody and RNAi, we further demonstrate that astrocytic laminin, by binding to integrin α2 receptor, prevents pericyte differentiation from the BBB-stabilizing resting stage to the BBB-disrupting contractile stage, and thus maintains the integrity of BBB. Additionally, loss of astrocytic laminin decreases aquaporin-4 (AQP4) and tight junction protein expression. Altogether, we report a critical role for astrocytic laminin in BBB regulation and pericyte differentiation. These results indicate that astrocytic laminin maintains the integrity of BBB through, at least in part, regulation of pericyte differentiation.

Original language	English (US)
Article number	3413
Pages (from-to)	3413
Number of pages	1
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4413
State	Published - 2014

Bibliographical note

Funding Information:
We thank Dr Arturo Alvaraz-Buylla for adenoviruses expressing Cre under GFAP promoter (Ad-pGFAP-Cre), Dr Jonathan Jones for the laminin a4 blocking antibody, Lee Cohen-Gould (Weill Cornell Medical School) and Dr Kunihiro Uryu (The Rockefeller University) for technical support and assistance with electron microscopy. We also thank the lab members of S.S. for scientific support and suggestions. This work was supported by NIH grant NS050537 to S.S., and Merck Postdoctoral Fellowship and BD Stem Cell Grant to Y.Y. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Publisher Copyright:
© 2014 Macmillan Publishers Limited.

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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title = "Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity",

abstract = "Blood brain barrier (BBB) breakdown is not only a consequence of but also contributes to many neurological disorders, including stroke and Alzheimer's disease. How the basement membrane (BM) contributes to the normal functioning of the BBB remains elusive. Here we use conditional knockout mice and an acute adenovirus-mediated knockdown model to show that lack of astrocytic laminin, a brain-specific BM component, induces BBB breakdown. Using functional blocking antibody and RNAi, we further demonstrate that astrocytic laminin, by binding to integrin α2 receptor, prevents pericyte differentiation from the BBB-stabilizing resting stage to the BBB-disrupting contractile stage, and thus maintains the integrity of BBB. Additionally, loss of astrocytic laminin decreases aquaporin-4 (AQP4) and tight junction protein expression. Altogether, we report a critical role for astrocytic laminin in BBB regulation and pericyte differentiation. These results indicate that astrocytic laminin maintains the integrity of BBB through, at least in part, regulation of pericyte differentiation. ",

author = "Yao Yao and Chen, {Zu Lin} and Norris, {Erin H.} and Sidney Strickland",

note = "Funding Information: We thank Dr Arturo Alvaraz-Buylla for adenoviruses expressing Cre under GFAP promoter (Ad-pGFAP-Cre), Dr Jonathan Jones for the laminin a4 blocking antibody, Lee Cohen-Gould (Weill Cornell Medical School) and Dr Kunihiro Uryu (The Rockefeller University) for technical support and assistance with electron microscopy. We also thank the lab members of S.S. for scientific support and suggestions. This work was supported by NIH grant NS050537 to S.S., and Merck Postdoctoral Fellowship and BD Stem Cell Grant to Y.Y. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited.",

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PY - 2014

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N2 - Blood brain barrier (BBB) breakdown is not only a consequence of but also contributes to many neurological disorders, including stroke and Alzheimer's disease. How the basement membrane (BM) contributes to the normal functioning of the BBB remains elusive. Here we use conditional knockout mice and an acute adenovirus-mediated knockdown model to show that lack of astrocytic laminin, a brain-specific BM component, induces BBB breakdown. Using functional blocking antibody and RNAi, we further demonstrate that astrocytic laminin, by binding to integrin α2 receptor, prevents pericyte differentiation from the BBB-stabilizing resting stage to the BBB-disrupting contractile stage, and thus maintains the integrity of BBB. Additionally, loss of astrocytic laminin decreases aquaporin-4 (AQP4) and tight junction protein expression. Altogether, we report a critical role for astrocytic laminin in BBB regulation and pericyte differentiation. These results indicate that astrocytic laminin maintains the integrity of BBB through, at least in part, regulation of pericyte differentiation.

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Astrocytic laminin regulates pericyte differentiation and maintains blood brain barrier integrity

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