Though radiation therapy plays a pivotal role in treatment of a wide range of brain tumors, the molecular mechanisms of adverse radiation effects following cranial irradiation (CR) is poorly understood.

     We explored the role of Bone Marrow Derived Progenitor Cells (BMDC) in response to cranial irradiation.

     

     Using co-culture experiments with BMDC and astrocytes, glioma and endothelial cells we established the protective role of BMDC against irradiation in a temporal and dose dependent manner. We used chimeric mice created by reconstituting the bone marrow (BM) of NOD/SCID mice with BM harvested from GFP transgenic mice. Intracranial windows (ICW) were created and with a stereotactic micro-irradiator fractionated or single radiation doses of (2 to 15 Gy) were delivered through the ICW to normal brain. Two-photon microscopy was used to obtain high-resolution real-time in-vivo images dynamically tracking GFP+ BMDCs intracranially. Mice were repeatedly imaged from 1hour to 30days CR. All mice were sacrificed using perfusion fixation and brains collected for correlative IHC and IF analysis.

     Our key novel findings are that a specific radiation and dose dependent recruitment of BMDCs occurs following CR. BMDC migrate outside the vessel lumen to encircle the vessel in part as smooth muscle cells, inflammatory cells and microglia, possibly providing a vascular support or reparative role. BMDC do not form EC or regulate de novo vessel formation.

     Only one specific cell line was studied.

     Our results for the first time confirm that inflammatory cells in response to CR are mobilized from the BM rather than being brain resident and most notably we provide evidence that recruited BMDC differentiate to form microglia. 

     More than 50% of microglia seen in response to CR are not resident microglia but recruited from the bone marrow.