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Biochemical re-programming of human dermal stem cells to neurons by increasing mitochondrial membrane potential

Cell Death & Differentiation (2018) | Download Citation

Abstract

Stem cells are generally believed to contain a small number of mitochondria, thus accounting for their glycolytic phenotype. We demonstrate here, however, that despite an indispensable glucose dependency, human dermal stem cells (hDSCs) contain very numerous mitochondria. Interestingly, these stem cells segregate into two distinct subpopulations. One exhibits high, the other low-mitochondrial membrane potentials (Δψm). We have made the same observations with mouse neural stem cells (mNSCs) which serve here as a complementary model to hDSCs. Strikingly, pharmacologic inhibition of phosphoinositide 3-kinase (PI3K) increased the overall Δψm, decreased the dependency on glycolysis and led to formation of TUJ1 positive, electrophysiologically functional neuron-like cells in both mNSCs and hDSCs, even in the absence of any neuronal growth factors. Furthermore, of the two, it was the Δψm-high subpopulation which produced more mitochondrial reactive oxygen species (ROS) and showed an enhanced neuronal differentiation capacity as compared to the Δψm-low subpopulation. These data suggest that the Δψm-low stem cells may function as the dormant stem cell population to sustain future neuronal differentiation by avoiding excessive ROS production. Thus, chemical modulation of PI3K activity, switching the metabotype of hDSCs to neurons, may have potential as an autologous transplantation strategy for neurodegenerative diseases.

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Edited by M Piacentini.

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Acknowledgements

We would like to thank Dr. Stefano Di Santo, Department of Neurosurgery, Research Unit, University of Bern, Switzerland, for his helpful discussions and technical assistance. This work was supported by the Swiss National Science Foundation (310030_166473 to HUS), Swiss Cancer league (KFS-3703-08-2015 to HUS), and European Union’s Horizon 2020 research and innovation program (Marie Sklodowska-Curie Grant No. 642295; MEL-PLEX). Images were acquired on equipment supported by the Microscopy Imaging Centre of the University of Bern.

Author contributions:

Conceptualization, HL and HUS; Methodology and Investigation, HL, ZYH, SLA, MFT, JSR, and SS; Materials and Reagents, RO, HRW, and HUS; Data Analysis and Interpretation, HL, ZYH, SLA, MFT, JSR, and HUS; Writing-Review and Editing, HL and HUS; Supervision, Project Administration and Funding Acquisition, HUS.

Author information

Author notes

    • Souzan Salemi

    Present address: Urologic Tissue Engineering and Stem Cell Therapy, Department of Urology, University Hospital Zurich, Frauenklinikstrasse 10, CH-8091, Zurich, Switzerland

  1. These authors contributed equally: Simon Leonhard April, Marcel Philipp Trefny.

Affiliations

  1. Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010, Bern, Switzerland

    • He Liu
    • , Zhaoyue He
    • , Simon Leonhard April
    • , Marcel Philipp Trefny
    • , Souzan Salemi
    •  & Hans-Uwe Simon
  2. Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3008, Bern, Switzerland

    • Jean-Sébastien Rougier
  3. University Hospital for Plastic and Hand Surgery, Bern University Hospital, Inselspital, CH-3010, Bern, Switzerland

    • Radu Olariu
  4. Department of Neurosurgery, Research Unit, University of Bern, Inselspital, CH-3010, Bern, Switzerland

    • Hans Rudolf Widmer

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Hans-Uwe Simon.

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https://doi.org/10.1038/s41418-018-0182-8