Hypoxia Epigenetically Confers Astrocytic Differentiation Potential on Human Pluripotent Cell-Derived Neural Precursor Cells

Summary 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.
Graphical Abstract
Highlights • Hypoxia-induced DNA demethylation allows hPSC-NPCs to differentiate into astrocytes • HIF1α and Notch signal activation play a critical role in this epigenetic change • RTT patient-derived astrocytes induced under hypoxia impair neuronal development
Human pluripotent stem cell-derived neural precursor cells (hNPCs) require long-term culturing to differentiate into astrocytes, retarding functional studies of human astrocytes. Nakashima and colleagues have developed a method for rapid induction of astrocytes from hNPCs cultured at low oxygen levels. Hypoxia induces epigenetic change, allowing hNPCs to differentiate into astrocytes. Their hypoxic culture should greatly accelerate research for disease-relevant astrocytes.