Comparison of the gene expression profiles of human fetal cortical astrocytes with pluripotent stem cell derived neural stem cells identifies human astrocyte markers and signaling pathways and transcription factors active in human astrocytes.

Nasir Malik,Xiantao Wang,Ming Zhan,Bin Yan,Mahendra Rao,Sonia Shah,Anastasia G. Efthymiou,Sabrina Heman-Ackah,Martin Pera

doi:10.1371/journal.pone.0096139

Abstract

Astrocytes are the most abundant cell type in the central nervous system (CNS) and have a multitude of functions that include maintenance of CNS homeostasis, trophic support of neurons, detoxification, and immune surveillance. It has only recently been appreciated that astrocyte dysfunction is a primary cause of many neurological disorders. Despite their importance in disease very little is known about global gene expression for human astrocytes. We have performed a microarray expression analysis of human fetal astrocytes to identify genes and signaling pathways that are important for astrocyte development and maintenance. Our analysis confirmed that the fetal astrocytes express high levels of the core astrocyte marker GFAP and the transcription factors from the NFI family which have been shown to play important roles in astrocyte development. A group of novel markers were identified that distinguish fetal astrocytes from pluripotent stem cell-derived neural stem cells (NSCs) and NSC-derived neurons. As in murine astrocytes, the Notch signaling pathway appears to be particularly important for cell fate decisions between the astrocyte and neuronal lineages in human astrocytes. These findings unveil the repertoire of genes expressed in human astrocytes and serve as a basis for further studies to better understand astrocyte biology, especially as it relates to disease.

Highlights

Astrocytes are process-bearing glial cells that comprise at least20–25% and possibly up to 50% of the total volume in some regions of the central nervous system (CNS)
Our goal was not to do a comprehensive survey of genes differentially expressed in astrocytes but identify clear astrocyte specific markers, core pathways and transcription factors important for astrocyte development and maintenance, and compare our results to those of previously published datasets
We reasoned that to achieve this goal for identifying astrocyte markers, each marker should be at least 5-fold enriched relative to neural stem cells (NSCs), be expressed in the other dataset of pluripotent stem cells (PSCs)-derived astrocytes, and have very low expression levels in other NSCderived neuronal and NSC gene expression datasets [18,20]

Summary

Introduction

Astrocytes are process-bearing glial cells that comprise at least20–25% and possibly up to 50% of the total volume in some regions of the central nervous system (CNS). Mouse knock-out studies have not been completely conclusive about the role of NFI and SOX genes in gliogenesis because of redundancy in these gene families but they do suggest that SOX9 and NFIA have a role in glial, astroglial, development [13,14]. Another pathway that has been shown to have a critical role is gliogenesis is the MAPK pathway which can regulate differentiation of astrocytes and oligodendrocytes through MEK activation [15]. It is likely that there is additional crosstalk between the transcription factors and signaling pathways described above that has yet to be elucidated

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