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Recovery of Neurovascular Unit Integrity by CDK5-KD Astrocyte Transplantation in a Global Cerebral Ischemia Model

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Abstract

Astrocytes play metabolic and structural support roles and contribute to the integrity of the blood-brain barrier (BBB), linking communication between neurons and the endothelium. Cyclin-dependent kinase 5 (CDK5) likely exerts a dual effect on the endothelium and astrocytes due to its involvement in migration and angiogenesis; the overactivation of CDK5 is associated with dysfunction in glutamate recapture and hypoxia. Recently, we proposed that CDK5-targeted astrocytes facilitate the recovery of neurological and motor function in transplanted ischemic rats. In the current study, we treated cerebral ischemic rats and endothelial cells exposed to glutamate toxicity with CDK5 knock-down (CDK5-KD) astrocytes to determine the role of CDK5 in neurovascular integrity. We found that the effects of CDK5-KD were sustained for 4 months, preventing neuronal and astrocyte loss, facilitating the recovery of the BBB via the production of BDNF by endogenous astrocytes (GFP−) surrounding vessels in the motor cortex and the corpus callosum of global ischemic rats, and improving neurological performance. These findings were supported by the in vitro findings of increased transendothelial resistance, p120-ctn+ adhesion and reduced intercellular gaps induced by a CDK5 inhibitor (roscovitine) in bEnd.3 cells in a glutamate-toxicity model. Additionally, CDK5-KD astrocytes in co-culture protected the endothelial cell viability, increased BDNF release from astrocytes, increased BDNF immunoreactivity in neighboring astrocytes and endothelial cells and enhanced cell adhesion in a glutamate-toxicity model. Altogether, these findings suggest that a CDK5 reduction in astrocytes protects the endothelium, which promotes BDNF release, endothelial adhesion, and the recovery of neurovascular unit integrity and brain function in ischemic rats.

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Acknowledgments

The authors thank Tania Marquez for assistance with the rat colonies at the SPF vivarium, Maria Alejandra Valencia for assistance with the behavior tests and histology assays, Juan Camilo Zuluaga for supporting the astrocyte characterization, Felipe Vargas for characterizing the endothelial cells, and Dr. Beverly Davidson from the Children Hospital of Philadelphia for her expert advice regarding the viral vectors.

Funding

This study was funded by grants from COLCIENCIAS: Code # 111554531400 (2012-2015), Banco de la República # 3.494 and CODI University of Antioquia 2014-970.

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Author notes

  1. Andrea Becerra-Calixto and Rafael Posada-Duque are contributed equally.

Authors and Affiliations

  1. Neuroscience Group of Antioquia, Cellular and Molecular Neurobiology Area, Faculty of Medicine, SIU, University of Antioquia, Calle 70, No. 52-21, Medellin, Colombia

    Andrea Becerra-Calixto, Rafael Posada-Duque & Gloria Patricia Cardona-Gómez

  2. Institute of Biology, Faculty of Exact and Natural Sciences, University of Antioquia, Medellin, Colombia

    Rafael Posada-Duque

  3. Universidad de Antioquia, Sede de Investigación Universitaria (SIU), Calle 62 # 52 – 59; Torre 1, Piso 4, Laboratorio 412, Medellín, Colombia

    Gloria Patricia Cardona-Gómez

Authors
  1. Andrea Becerra-Calixto
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  2. Rafael Posada-Duque
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  3. Gloria Patricia Cardona-Gómez
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Corresponding author

Correspondence to Gloria Patricia Cardona-Gómez.

Ethics declarations

All animal procedures were performed in accordance with the ARRIVE guidelines, the Guide for the Care and Use of Laboratory Animals, 8th edition, published by the National Institutes of Health (NIH) and Colombian standards (law 84/1989 and resolution 8430/1993). These procedures were approved by the Ethics Committee for Animal Experimentation at the University of Antioquia, Medellín, Colombia.

Conflicts of Interest

The authors declare that they have no conflict of interest.

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MAIN POINTS

CDK5-KD astrocyte transplantation following stroke maintains neurological and motor skills for 4 months. This neuroprotection is supported by the production of BDNF from astrocytes and its effects on endothelial cells, preserving the neurovascular unit integrity.

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Becerra-Calixto, A., Posada-Duque, R. & Cardona-Gómez, G.P. Recovery of Neurovascular Unit Integrity by CDK5-KD Astrocyte Transplantation in a Global Cerebral Ischemia Model. Mol Neurobiol 55, 8563–8585 (2018). https://doi.org/10.1007/s12035-018-0992-1

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  • DOI: https://doi.org/10.1007/s12035-018-0992-1

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