(IMAGE)
Caption
Neural stem cells (NSCs) produce neurons and glial cells (astrocytes and oligodendrocytes), which are major cells in the brain. NSCs are maintained and expanded by self-renewal in order to avoid depletion during neurogenesis and astrogliogenesis. During midgestation, NSCs reside under hypoxia partly due to immature vasculature. The mechanisms by which NSCs efficiently self-renew under such circumstances have not fully been discovered. To tackle these problems, we first isolated NSCs from midgestation mouse brains and cultured them under the hypoxic condition. Neurosphere formation under the hypoxic condition was dramatically increased compared that under the normoxic condition. Since neurosphere formation is a good indicator of the presence of NSCs, this result suggests a mechanism to maintain NSCs under hypoxia. Our further study surprisingly showed that NSCs cultured under hypoxia secreted vascular endothelial growth factor A (VEGF-A) and its amount was sufficient to induce NSC self-renewal. The experiments such as that using a VEGF-A inhibitor suggest that VEGF-A secreted from NSCs under the hypoxia promotes NSC self-renew and contributes to maintenance and expansion of NSCs. Our results suggest that NSCs have adaptive potential to respond to hypoxia to organize self-advantageous niche involving VEGF-A when the vascular system is immature. This study will help to elucidate mechanisms underlying not only NSC maintenance but also vascular formation in the brain at the embryonic stages since VEGF-A is an important factor for vasculature development.
Credit
Department of Stem Cell Regulation, TMDU
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