Jun 9, 2017

Hypoxia epigenetically confers astrocytic differentiation potential on human pluripotent cell-derived neural precursor cells

The research group led by Dr. Nakashima from the Graduate School of Medical Sciences, Kyushu University found hypoxic condition confers astrocyte differentiation ability on human pluripotent cell-derived neural precursor cells.

Human neural precursor cells derived from pluripotent stem cells (hPSC-hNPCs) 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 hPSC-hNPCs remain elusive. Here, the research group show that hypoxia confers astrocytic differentiation potential on hPSC-hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia-inducible factor 1 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 hPSC-hNPCs, and that these astrocytes impaired neuronal development. Thus, this group’s findings shed further light on the molecular mechanisms regulating hPSC-hNPCs differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders.

Figure. In hPSC-hNPCs, astrocytic genes are highly methylated, limiting their potential to differentiate into astrocytes. However, when they are cultured in hypoxic condition, HIF1α together with Notch intracellular domain (NICD) efficiently induced Notch-signal target genes including nuclear factor I (NFI), which is known to induce demethylation of astrocytic genes. This demethylation confers astrocytic potential on hPSC-hNPCs.

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Press release

Stem Cell Reports