TY - JOUR
T1 - Hypoxia Epigenetically Confers Astrocytic Differentiation Potential on Human Pluripotent Cell-Derived Neural Precursor Cells
AU - Yasui, Tetsuro
AU - Uezono, Naohiro
AU - Nakashima, Hideyuki
AU - Noguchi, Hirofumi
AU - Matsuda, Taito
AU - Noda-Andoh, Tomoko
AU - Okano, Hideyuki
AU - Nakashima, Kinichi
N1 - Funding Information:
We appreciate the technical assistance from The Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences. We have greatly benefited from discussions with J. Kohyama, S. Katada, and T. Imamura. We thank A. Smith for providing the human NPCs (CB660, AF22-24), and I. Smith for editing the manuscript. This work was supported by grants from the Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), JSPS KAKENHI (15K14452), MEXT KAKENHI (16H06527), and the Uehara Memorial Foundation to K.N.
Publisher Copyright:
© 2017 The Author(s)
PY - 2017/6/6
Y1 - 2017/6/6
N2 - Human neural precursor cells (hNPCs) derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia-inducible factor 1α and Notch signaling, accompanied by a reduction of DNA methylation level in the promoter region of a typical astrocyte-specific gene, Glial fibrillary acidic protein. Furthermore, we found that this hypoxic culture condition could be applied to rapid generation of astrocytes from Rett syndrome patient-derived hNPCs, and that these astrocytes impaired neuronal development. Thus, our findings shed further light on the molecular mechanisms regulating hNPC differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders.
AB - Human neural precursor cells (hNPCs) derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia-inducible factor 1α and Notch signaling, accompanied by a reduction of DNA methylation level in the promoter region of a typical astrocyte-specific gene, Glial fibrillary acidic protein. Furthermore, we found that this hypoxic culture condition could be applied to rapid generation of astrocytes from Rett syndrome patient-derived hNPCs, and that these astrocytes impaired neuronal development. Thus, our findings shed further light on the molecular mechanisms regulating hNPC differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders.
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U2 - 10.1016/j.stemcr.2017.05.001
DO - 10.1016/j.stemcr.2017.05.001
M3 - Article
C2 - 28591654
AN - SCOPUS:85020315491
VL - 8
SP - 1743
EP - 1756
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 6
ER -