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72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

06.06. - 09.06.2021

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Implementation of a novel humanised ex-vivo brain slice model to study glioblastoma and glioma-associated microglia

Entwicklung eines neuartigen humanisierten ex-vivo Hirnschnittmodells zur Untersuchung von Glioblastomen und gliom-assoziierten Mikroglia

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  • Cynthia Nanvuma - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Yimin Huang - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland; Charité Universitätsmedizin, Berlin, Deutschland
  • Edyta Motta - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Leonard Kuhrt - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland; Charité Universitätsmedizin, Berlin, Deutschland
  • Yang Yuan - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Malgorzata Lubas - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Pengfei Xia - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Shuai Zhu - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Marina Schnauss - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland; Charité Universitätsmedizin, Berlin, Deutschland
  • Feng Hu - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Michael Synowitz - University Hospital of Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Deutschland
  • presenting/speaker Charlotte Flüh - University Hospital of Schleswig-Holstein, Campus Kiel, Department of Neurosurgery, Kiel, Deutschland; Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland
  • Helmut Kettenmann - Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Cellular Neurosciences, Berlin, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie. sine loco [digital], 06.-09.06.2021. Düsseldorf: German Medical Science GMS Publishing House; 2021. DocV157

doi: 10.3205/21dgnc152, urn:nbn:de:0183-21dgnc1529

Published: June 4, 2021

© 2021 Nanvuma et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Objective: Glioblastoma multiforme is a highly malignant brain tumor. Resection followed by radio-chemotherapy leads to an overall survival of only 15 months. Up to 40% of the tumor mass consist of tumor-associated microglia and macrophages (TAMs). These cells were shown to promote tumor growth and invasiveness in many murine glioma models. The interaction between TAMs and tumor cells is crucial for tumor progression and includes several known pathways. Still, murine glioma models only partially mirror the human tumor microenvironment. Several known genes, which are highly upregulated in human glioma and TAMs are only expressed in human tissue and not in mice. To further investigate some of these genes, we aimed at establishing a humanized ex-vivo brain slice model, in which human TAMs and human glioma cells can be studied in a standardized manner.

Methods: We used 250 µm thick murine brain slices, which were depleted of intrinsic microglia by applying clodoronated liposomes. Next, we inoculated human glioma cells (originating from the cell lines U87, U251MG, LN229 and several patient derived cells lines) with or without human microglia derived from induced pluripotent stem cells (iPSCs). Slices were cultivated for 7 to 14 days. We then performed a detailed analysis of microglia morphology (sphericity, cell body volume, process length and branching pattern) and tumor volume.

Results: Clodronation efficacy was high, depending on duration of treatment and length of cultivation. iPSCs and tumor cells integrated into the slice very well. The presence of tumor cells led to an increased sphericity of iPSC-dervied microglia and to an increased cell body volume. Tumor volume was significantly larger when iPSC-derived microglia were present. This was found in various glioma cells lines and also in patient derived cells.

Conclusion: The newly established humanized ex-vivo brain slice system was shown to be feasible. The method successfully allows to study the interaction between human TAMs and tumor cells. Microglia foster tumor growth not only in murine glioma models, but also in a human paradigm. The humanized ex-vivo brain slice model therefore is the optimal basis to study the role human-specific genes in TAM-glioma interaction.