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Transforming growth factor α promotes sequential conversion of mature astrocytes into neural progenitors and stem cells

Oncogene volume 26, pages 2695–2706 (2007)Cite this article

Abstract

An instability of the mature cell phenotype is thought to participate to the formation of gliomas, primary brain tumors deriving from astrocytes and/or neural stem cells. Transforming growth factor α (TGFα) is an erbB1 ligand overexpressed in the earliest stages of gliomas, and exerts trophic effects on gliomal cells and astrocytes. Here, we questioned whether prolonged TGFα exposure affects the stability of the normal mature astrocyte phenotype. We first developed astrocyte cultures devoid of residual neural stem cells or progenitors. We demonstrate that days of TGFα treatment result in the functional conversion of a population of mature astrocytes into radial glial cells, a population of neural progenitors. TGFα-generated radial glial cells support embryonic neurons migration, and give birth to cells of the neuronal lineage, expressing neuronal markers and the electrophysiological properties of neuroblasts. Lengthening TGFα treatment to months results in the delayed appearance of cells with neural stem cells properties: they form floating cellular spheres that are self-renewing, can be clonally derived from a single cell and differentiated into cells of the neuronal lineage. This study uncovers a novel population of mature astrocytes capable, in response to a single epigenetic factor, to regress progressively into a neural stem-like cell stage via an intermediate progenitor stage.

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Acknowledgements

We are grateful to Dr Leprince and Dr Heintz for their generous gifts of RC2 and BLBP antibodies, respectively and to Dr Dusart for providing us with actin-GFP transgenic mice. We warmly thank Professor Glowinski, Dr Abrous, Dr Barneoud and Dr Mallat for their constant support, Dr Koulakoff and Dr Eichmann for generously sharing their knowledge and equipments, and Amelia Dias-Morais, Anne Loyens and Eric Etienne for expert technical help. This research was supported by the Association pour la Recherche contre le Cancer (ARC, Grant# 3500 to HC, and study fellowship to AS) and the Fondation pour la Recherche Médicale (FRM grant to VP).

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Authors and Affiliations

  1. Inserm U114 and U752, Paris, France

    A Sharif, L Romao, J-M Studler, H Chneiweiss & M-P Junier

  2. University of Paris 5, Paris, France

    A Sharif, L Romao, J-M Studler, H Chneiweiss & M-P Junier

  3. UMR CNRS 7102, University Pierre et Marie Curie, Paris, France

    P Legendre

  4. Inserm U816, Lille, France

    V Prévot & C Allet

  5. Departamento de Anatomia, Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude, Rio de Janeiro, RJ, Brazil

    L Romao

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  1. A Sharif
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Correspondence to M-P Junier.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Sharif, A., Legendre, P., Prévot, V. et al. Transforming growth factor α promotes sequential conversion of mature astrocytes into neural progenitors and stem cells. Oncogene 26, 2695–2706 (2007). https://doi.org/10.1038/sj.onc.1210071

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