Acta Neuropathologica

, Volume 125, Issue 4, pp 609–620 | Cite as

GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis

  • Min-Chi Ku
  • Susanne A. Wolf
  • Dorota Respondek
  • Vitali Matyash
  • Andreas Pohlmann
  • Sonia Waiczies
  • Helmar Waiczies
  • Thoralf Niendorf
  • Michael Synowitz
  • Rainer Glass
  • Helmut Kettenmann
Original Paper


High-grade gliomas are the most common primary brain tumors. Their malignancy is promoted by the complex crosstalk between different cell types in the central nervous system. Microglia/brain macrophages infiltrate high-grade gliomas and contribute to their progression. To identify factors that mediate the attraction of microglia/macrophages to malignant brain tumors, we established a glioma cell encapsulation model that was applied in vivo. Mouse GL261 glioma cell line and human high-grade glioma cells were seeded into hollow fibers (HF) that allow the passage of soluble molecules but not cells. The glioma cell containing HF were implanted into one brain hemisphere and simultaneously HF with non-transformed fibroblasts (controls) were introduced into the contralateral hemisphere. Implanted mouse and human glioma- but not fibroblast-containing HF attracted microglia and up-regulated immunoreactivity for GFAP, which is a marker of astrogliosis. In this study, we identified GDNF as an important factor for microglial attraction: (1) GL261 and human glioma cells secret GDNF, (2) reduced GDNF production by siRNA in GL261 in mouse glioma cells diminished attraction of microglia, (3) over-expression of GDNF in fibroblasts promoted microglia attraction in our HF assay. In vitro migration assays also showed that GDNF is a strong chemoattractant for microglia. While GDNF release from human or mouse glioma had a profound effect on microglial attraction, the glioma-induced astrogliosis was not affected. Finally, we could show that injection of GL261 mouse glioma cells with GDNF knockdown by shRNA into mouse brains resulted in reduced tumor expansion and improved survival as compared to injection of control cells.


Glioblastoma Microglia GDNF Astrocyte 



This work was supported by the graduate school of NeuroCure at the Charité, Berlin, (stipend to M. C. Ku) and by Deutsche Forschungsgemeinschaft (TR 43). We are thankful to Prof. Carlos Ibanez for providing GDNF cDNA construct for transfection and Prof. Jochen Meier for providing human brain tissue. We thank Dr. Zoltan Cseresnyes and Dr. Anje Sporbert for technical assistance with confocal microscopy. We appreciate the support of Babette Dieringer for MR imaging and Maria Pannell for manuscript proof reading.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

401_2013_1079_MOESM1_ESM.tif (843 kb)
Supplemental Fig. 1 Time course of GL261 cell proliferation after siRNA transfection and encapsulated into HF was estimated using an Alamar blue assay. The results represent the mean ± s.e.m. from 5 fibers (TIFF 843 kb)
401_2013_1079_MOESM2_ESM.tif (5.3 mb)
Supplemental Fig. 2 a GDNF secretion from non-targeted shRNA treated GL261 cells (shNT) and GDNF shRNA treated cells (shGDNF) after one month of transfection was analyzed by ELISA (*p < 0.05). b After transfection with either shNT (left panel) or shGDNF (right panel), GL261 cells enclosed in HF were implanted into the mouse brains (left and right hemisphere, respectively). After 6 days of implantation, mice were sacrificed and brain sections were stained with Iba-1 (red) antibody. Cell nuclei were counterstained with DAPI (blue). Yellow dashed line indicates the border between HF and brain tissue. c Density of microglia surrounding HF with shGDNF transfected GL261 cells is shown (mean ± s.e.m. n = 5 mice; **p < 0.01) compared with control shNT GL261 cells. (TIFF 5381 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Min-Chi Ku
    • 1
  • Susanne A. Wolf
    • 1
  • Dorota Respondek
    • 1
  • Vitali Matyash
    • 1
  • Andreas Pohlmann
    • 2
  • Sonia Waiczies
    • 2
  • Helmar Waiczies
    • 2
  • Thoralf Niendorf
    • 2
  • Michael Synowitz
    • 3
  • Rainer Glass
    • 4
  • Helmut Kettenmann
    • 1
  1. 1.Department of Cellular Neuroscience, Max Delbrück Center for Molecular Medicine (MDC)BerlinGermany
  2. 2.Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine (MDC)BerlinGermany
  3. 3.Department of NeurosurgeryCharité-Universitätsmedizin BerlinBerlinGermany
  4. 4.Klinikum der Universität München (LMU), Klinik für Neurochirurgie, Neurochirurgische ForschungMunichGermany

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