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Hypoxia upregulates aldehyde dehydrogenase isoform 1 (ALDH1) expression and induces functional stem cell characteristics in human glioblastoma cells

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Abstract

Aldehyde dehydrogenase 1 (ALDH1) has been used to isolate tumorigenic stem-like cells in a large number of tumors, including glioblastoma multiforme (GBM). We recently showed that human glioblastoma cells with high ALDH1 (ALDH1high) activity contain stem-cell-like characteristics. In the study reported here, we isolated established and primary human glioblastoma cells based on their ALDH1 expression. When tested for asymmetric division, only cells with ALDH1high expression were able to restore heterogeneous populations after a few days, whereas cells with ALDH1low levels could not. Most interestingly, the capacity of cells with ALDH1low levels to divide asymmetrically into cells with either ALDH1high or ALDH1low expression could be restored after exposure to hypoxic culture conditions. Consequently, we found neurosphere formation reinstated in posthypoxic, formerly ALDH1low, cells. The direct involvement of ALDH1 could be confirmed by ALDH1 small hairpin ribonucleic acid (shRNA) knockdown, suggesting ALDH1 as an intracellular marker for the identification and isolation of stem-like glioblastoma cells. In summary, we show that ALDH1 expression correlates well with asymmetric division capacity and tumor sphere formation. Furthermore, we demonstrated that hypoxic culture conditions induce and/or upregulate ALDH1 expression in established and primary GBM cell lines.

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Acknowledgments

The authors express sincere gratitude to Lynette Henkel from the FACS core facility for her expert help with cell sorting, as well as gratitude to all involved physicians, nurses, and technicians. This research was funded by the SFB 824 of Deutsche Forschungsgemeinschaft (DFG). The authors gratefully acknowledge the support of the TUM Graduate School’s Faculty Graduate Centre of Medicine at Technische Universität München, Germany.

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Authors and Affiliations

  1. Division of Neuropathology, Institute of Pathology, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany

    Eric Soehngen, Andrea Schaefer, Julia Koeritzer, Velia Huelsmeyer & Juergen Schlegel

  2. Institute of Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany

    Eric Soehngen & Claus Zimmer

  3. Max-Planck-Institute for Extraterrestrial Physics, Garching, Germany

    Julia Koeritzer

  4. Department of Neurosurgery, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Strasse 22, 81675, Munich, Germany

    Florian Ringel & Jens Gempt

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  1. Eric Soehngen
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Correspondence to Eric Soehngen.

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Soehngen, E., Schaefer, A., Koeritzer, J. et al. Hypoxia upregulates aldehyde dehydrogenase isoform 1 (ALDH1) expression and induces functional stem cell characteristics in human glioblastoma cells. Brain Tumor Pathol 31, 247–256 (2014). https://doi.org/10.1007/s10014-013-0170-0

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