Unique gene expression patterns indicate microglial contribution to neural stem cell recovery following irradiation.

Ionizing radiation results in damage to neural stem cells and reduced neurogenesis. The aim of the present study was to determine intrinsic and extrinsic factors that influence neural stem cell survival following irradiation, using qPCR. Gene expression of hippocampal and SVZ neurospheres were analyzed following irradiation, and results demonstrated that irradiated hippocampal and SVZ stem cells displayed similar gene expression profiles for intrinsic genes. Irradiated microglia (extrinsic factor) isolated from the SVZ exhibited increased gene expression of growth factors involved in stem cell maintenance, proliferation, and survival. However, microglial genes in the irradiated hippocampus responded less favorably with respect to stem cell recovery. This might explain the superior recovery of SVZ compared to hippocampal stem cells following in vivo irradiation. In addition, our results show that a combination of growth factors, which were upregulated in SVZ microglia, increased the proliferation and decreased cell death of irradiated neurospheres in vitro.

Synergetic effects of granulocyte-colony stimulating factor and cognitive training on spatial learning and survival of newborn hippocampal neurons.

Granulocyte-Colony Stimulating Factor (G-CSF) is an endogenous hematopoietic growth factor known for its role in the proliferation and differentiation of cells of the myeloic lineage. Only recently its significance in the CNS has been uncovered. G-CSF attenuates apoptosis and controls proliferation and differentiation of neural stem cells. G-CSF activates upstream kinases of the cAMP response element binding protein (CREB), which is thought to facilitate the survival of neuronal precursors and to recruit new neurons into the dentate gyrus. CREB is also essential for spatial long-term memory formation. To assess the role and the potential of this factor on learning and memory-formation we systemically administered G-CSF in rats engaged in spatial learning in an eight-arm radial maze. G-CSF significantly improved spatial learning and increased in combination with cognitive training the survival of newborn neurons in the hippocampus as measured by bromodeoxyuridine and doublecortin immunohistochemistry. Additionally, G-CSF improved re-acquisition of spatial information after 26 days. These findings support the hypothesis that G-CSF can enhance learning and memory formation. Due to its easy applicability and its history as a well-tolerated hematological drug, the use of G-CSF opens up new neurological treatment opportunities in conditions where learning and memory-formation deficits occur.

Differential recovery of neural stem cells in the subventricular zone and dentate gyrus after ionizing radiation.

Radiation therapy is a widely used treatment for malignant central nervous system tumors. Mature neurons are terminally differentiated, whereas stem and progenitor cells have a prominent proliferative capacity and are therefore highly vulnerable to irradiation. Our aim was to investigate how cranial radiation in young rats would affect stem/progenitor cells in the two niches of adult neurogenesis, the subventricular zone (SVZ) and the dentate gyrus of the hippocampal formation. Nine weeks after irradiation we found that in irradiated animals, hippocampal neurogenesis was reduced to 5% of control levels. Similarly, the numbers of actively proliferating cells and radial glia-like stem cells (nestin+/glial fibrillary acidic protein [GFAP]+) in the dentate gyrus were reduced to 10% and 15% of control levels, respectively. In the irradiated olfactory bulb, neurogenesis was reduced to 40% of control levels, and the number of actively proliferating cells in the SVZ was reduced to 53% of control levels. However, the number of nestin+/GFAP+ cells in the SVZ was unchanged compared with controls. To evaluate the immediate response to the radiation injury, we quantified the amount of proliferation in the SVZ and dentate gyrus 1 day after irradiation. We found an equal reduction in proliferating cells both in dentate gyrus and SVZ. In summary, we show an initial response to radiation injury that is similar in both brain stem cell niches. However, the long-term effects on stem cells and neurogenesis in these two areas differ significantly: the dentate gyrus is severely affected long-term, whereas the SVZ appears to recover with time.

Peripheral infusion of insulin-like growth factor-I increases the number of newborn oligodendrocytes in the cerebral cortex of adult hypophysectomized rats.

We have previously shown that recombinant human (rh) IGF-I induces cell proliferation and neurogenesis in the hippocampus of hypophysectomized rats. In the current investigation, we determined the effects of rhIGF-I on proliferation and differentiation in the cerebral cortex. Adult hypophysectomized rats were injected with bromodeoxyuridine (BrdU) to label newborn cells (once a day for the first 5 d), and rhIGF-I was administered peripherally for 6 or 20 d. In the cerebral cortex, the number of BrdU-labeled cells increased after 20 d but not after 6 d of rhIGF-I infusion. This suggests that rhIGF-I enhances the survival of newborn cells in the cerebral cortex. Using BrdU labeling combined with the oligodendrocyte-specific markers myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase, we demonstrated an increase in oligodendrogenesis in the cerebral cortex. The total amount of myelin basic protein and 2',3'-cyclic nucleotide 3'-phosphodiesterase was also increased on Western blots of homogenates of the cerebral cortex, confirming the immunohistochemical findings. Also, we observed an increase in the number of capillary-associated BrdU-positive cells, although total capillary area was not increased. rhIGF-I treatment did not affect cortical astrogliogenesis and neurogenesis was not observed. The ability of rhIGF-I to induce cortical oligodendrogenesis may have implications for the regenerative potential of the cortex.