TY - JOUR
T1 - Hypoxia stimulates neural stem cell proliferation by increasing HIF-1α expression and activating Wnt/β-catenin signaling
AU - Qi, C.
AU - Zhang, J.
AU - Chen, X.
AU - Wan, J.
AU - Wang, J.
AU - Zhang, P.
AU - Liu, Y.
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (No. 30960107, 81070998), the Natural Science Foundation of Qinghai province of China (No.2013-Z-727), and NIH R01NS078026 and R01AT007317. The authors thanks China Scholarship Council supported to visiting Johns Hopkins University (201308635039).The authors thank Jiarui Wang and Claire Levine for assistance with manuscript preparation.
Publisher Copyright:
© 2017 by the C.M.B. Association.
PY - 2017
Y1 - 2017
N2 - Evidence indicates that after brain injury, neurogenesis is enhanced in regions such as hippocampus, striatum, and cortex. To study the role of hypoxia-inducible factor-1 (HIF-1α) and Wnt signaling in cerebral ischemia/hypoxia-induced proliferation of neural stem cells (NSCs), we investigated the proliferation of NSCs, expression of HIF-1α, and activation of Wnt signaling under conditions of pathologic hypoxia in vitro. NSCs were isolated from 30-day-old Sprague-Dawley rats and subjected to 0.3% oxygen in a microaerophilic incubation system. Cell proliferation was evaluated by measuring the diameter of neurospheres and by bromodeoxyuridine incorporation assays. Real-time quantitative PCR and Western blotting were used to detect mRNA and protein levels of HIF-1α, β-catenin, and cyclin D1 in the NSCs. The results showed that hypoxia increased NSC proliferation and the levels of HIF-1α, β-catenin, and cyclin D1 (p < 0.05). Blockade of the Wnt signaling pathway decreased hypoxia-induced NSC proliferation, whereas activation of this pathway increased hypoxia-induced NSC proliferation (p < 0.05). Knockdown of HIF-1α with HIF-1α siRNA decreased β-catenin nuclear translocation and cyclin D1 expression, and inhibited proliferation of NSCs (p < 0.05). These findings indicate that pathologic hypoxia stimulates NSC proliferation by increasing expression of HIF-1α and activating the Wnt/β-catenin signaling pathway. The data suggest that Wnt/β-catenin signaling may play a key role in NSC proliferation under conditions of pathologic hypoxia.
AB - Evidence indicates that after brain injury, neurogenesis is enhanced in regions such as hippocampus, striatum, and cortex. To study the role of hypoxia-inducible factor-1 (HIF-1α) and Wnt signaling in cerebral ischemia/hypoxia-induced proliferation of neural stem cells (NSCs), we investigated the proliferation of NSCs, expression of HIF-1α, and activation of Wnt signaling under conditions of pathologic hypoxia in vitro. NSCs were isolated from 30-day-old Sprague-Dawley rats and subjected to 0.3% oxygen in a microaerophilic incubation system. Cell proliferation was evaluated by measuring the diameter of neurospheres and by bromodeoxyuridine incorporation assays. Real-time quantitative PCR and Western blotting were used to detect mRNA and protein levels of HIF-1α, β-catenin, and cyclin D1 in the NSCs. The results showed that hypoxia increased NSC proliferation and the levels of HIF-1α, β-catenin, and cyclin D1 (p < 0.05). Blockade of the Wnt signaling pathway decreased hypoxia-induced NSC proliferation, whereas activation of this pathway increased hypoxia-induced NSC proliferation (p < 0.05). Knockdown of HIF-1α with HIF-1α siRNA decreased β-catenin nuclear translocation and cyclin D1 expression, and inhibited proliferation of NSCs (p < 0.05). These findings indicate that pathologic hypoxia stimulates NSC proliferation by increasing expression of HIF-1α and activating the Wnt/β-catenin signaling pathway. The data suggest that Wnt/β-catenin signaling may play a key role in NSC proliferation under conditions of pathologic hypoxia.
KW - Hypoxia inducible factor-1 alpha
KW - Neural stem cells
KW - Neurogenesis
KW - Wnt
UR - http://www.scopus.com/inward/record.url?scp=85030623541&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030623541&partnerID=8YFLogxK
U2 - 10.14715/cmb/2017.63.7.2
DO - 10.14715/cmb/2017.63.7.2
M3 - Article
C2 - 28838333
AN - SCOPUS:85030623541
SN - 0145-5680
VL - 63
SP - 12
EP - 19
JO - Cellular and Molecular Biology
JF - Cellular and Molecular Biology
IS - 7
ER -