Article
In vitro system to dissect the molecular basis of vanilloid/TRPV1 mediated anti-tumoral activity of human neural progenitor cells in glioblastoma multiforme
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Authors
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Luis Azmitia
- Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland
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Ramazan Uyar
- Ludwig-Maximilians-Universität München, Neurochirurgische Klinik und Poliklinik, Neurochirurgische Forschung, München, Deutschland
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Roland Kälin
- Ludwig-Maximilians-Universität München, Neurochirurgische Klinik und Poliklinik, Neurochirurgische Forschung, München, Deutschland
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Björn Brändl
- Universitätsklinikum Schleswig-Holstein, Zentrum für Integrative Psychiatrie, Labor für Integrative Biologie, Kiel, Deutschland
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Franz Müller
- Universitätsklinikum Schleswig-Holstein, Zentrum für Integrative Psychiatrie, Labor für Integrative Biologie, Kiel, Deutschland
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Rainer Glaß
- Ludwig-Maximilians-Universität München, Neurochirurgische Klinik und Poliklinik, Neurochirurgische Forschung, München, Deutschland
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Michael Synowitz
- Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland
| Published: | June 9, 2017 |
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Outline
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Objective: Malignant gliomas (GBM) are the most frequent primary brain tumor in adults, with no curative therapy and an average survival rate of 15 months (Curado et al. 2007). It has been shown that endogenous vanilloids (fatty acid amides) secreted by neural progenitor cells induce cytotoxicity in GBM cells. This anti-tumoral effect appears to be mediated by the direct stimulation of the Transient Receptor Potential Vanilloid 1 (TRPV1,) specifically present on GBM cells. As neural progenitors represent only a small and difficult to access cell population in the adult human brain we turned to neural progenitors differentiated from human induced pluripotent stem cells as well as directly induced from fibroblasts as in vitro models for dissecting Vanilloid-mediated anti-tumoral activity in humans.
Methods: Human induced pluripotent stem cells (iPSCs) were differentiated into long-term expandable neural stem cells (lt-NSCs) following published protocols {Koch:2009cw} and we directly reprogrammed patient derived fibroblasts into induced NPCs (iNSCs) with a viral free insertion method. Both lt-NSC and iNSCs were expandable, expressed NPCs markers (at genomic and protein level), differentiated into mature neurons and glial cells, showed a stable karyotype and had active membrane potentials.
Results: Human primary glioma initiating cells (GICs) were exposed to conditioned media from both lt-NSC and iNSCs. We observed an increased cell death in GICs. Exposure of TRPV1-deficient GICs to the same conditioned media preparations resulted in an attenuated cytotoxic response, suggesting an involvement of endogenous vanilloids secreted by lt-NSC and iNSC in the observed GBM cell death.
Conclusion: In summary, we have established a human in vitro model with two different source for human neural progenitors in order to molecularly dissect vanilloid-mediated GBM cytotoxicity. This system may be either exploited via transplanted, isogenic neural progenitors in GBM patients or, more ideally, used to identify metablic pathways leading to the synthesis of individual, highly bioactive endogenous vanilloids as potential chemotherapeutic agents for the treatment of GBMs.
