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Astrocytes Can Adopt Endothelial Cell Fates in a p53-Dependent Manner

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Abstract

Astrocytes respond to a variety of CNS injuries by cellular enlargement, process outgrowth, and upregulation of extracellular matrix proteins that function to prevent expansion of the injured region. This astrocytic response, though critical to the acute injury response, results in the formation of a glial scar that inhibits neural repair. Scar-forming cells (fibroblasts) in the heart can undergo mesenchymal-endothelial transition into endothelial cell fates following cardiac injury in a process dependent on p53 that can be modulated to augment cardiac repair. Here, we sought to determine whether astrocytes, as the primary scar-forming cell of the CNS, are able to undergo a similar cellular phenotypic transition and adopt endothelial cell fates. Serum deprivation of differentiated astrocytes resulted in a change in cellular morphology and upregulation of endothelial cell marker genes. In a tube formation assay, serum-deprived astrocytes showed a substantial increase in vessel-like morphology that was comparable to human umbilical vein endothelial cells and dependent on p53. RNA sequencing of serum-deprived astrocytes demonstrated an expression profile that mimicked an endothelial rather than astrocyte transcriptome and identified p53 and angiogenic pathways as specifically upregulated. Inhibition of p53 with genetic or pharmacologic strategies inhibited astrocyte-endothelial transition. Astrocyte-endothelial cell transition could also be modulated by miR-194, a microRNA downstream of p53 that affects expression of genes regulating angiogenesis. Together, these studies demonstrate that differentiated astrocytes retain a stimulus-dependent mechanism for cellular transition into an endothelial phenotype that may modulate formation of the glial scar and promote injury-induced angiogenesis.

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Acknowledgments

We acknowledge the support of the National Institute of Neurological Disorders and Stroke (NINDS) Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691). JDH is supported by (NINDS) NS083740. AD is supported by National Heart, Lung, and Blood Institute (NHLBI) HL129178.

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Authors and Affiliations

  1. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, 635 Charles E. Young Dr. South, Rm 415, Los Angeles, CA, 90095, USA

    Andrew J. Brumm, Stefanie Nunez, Mehdi M. Doroudchi, S. Thomas Carmichael & Jason D. Hinman

  2. Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA

    Riki Kawaguchi

  3. Division of Cardiology, Department of Medicine, Broad Stem Cell Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Jinhzu Duan & Arjun Deb

  4. Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California Los Angeles, Los Angeles, CA, USA

    Matteo Pellegrini & Larry Lam

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  1. Andrew J. Brumm
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  2. Stefanie Nunez
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  4. Riki Kawaguchi
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Correspondence to Arjun Deb or Jason D. Hinman.

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Brumm, A.J., Nunez, S., Doroudchi, M.M. et al. Astrocytes Can Adopt Endothelial Cell Fates in a p53-Dependent Manner. Mol Neurobiol 54, 4584–4596 (2017). https://doi.org/10.1007/s12035-016-9974-3

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