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Ferrodifferentiation regulates neurodevelopment via ROS generation

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Abstract

Iron is important for life, and iron deficiency impairs development, but whether the iron level regulates neural differentiation remains elusive. In this study, with iron-regulatory proteins (IRPs) knockout embryonic stem cells (ESCs) that showed severe iron deficiency, we found that the Pax6- and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1−/−IRP2−/− ESCs were significantly decreased after inducing neural differentiation. Consistently, in vivo study showed that the knockdown of IRP1 in IRP2−/− fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons. These findings suggest that low intracellular iron status significantly inhibits neurodifferentiation. When supplementing IRP1−/−IRP2−/− ESCs with iron, these ESCs could differentiate normally. Further investigations revealed that the underlying mechanism was associated with an increase in reactive oxygen species (ROS) production caused by the substantially low level of iron and the down-regulation of iron-sulfur cluster protein ISCU, which, in turn, affected the proliferation and differentiation of stem cells. Thus, the appropriate amount of iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation.

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Data availability

All relevant data in this study are available from the corresponding author (yzchang@hebtu.edu.cn) upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (30871260), the Natural Science Foundation of Hebei Province (E2021205003, C2019206575) and the Science and Technology Project of Hebei Education Department (QN2019005, BJK2022049).

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Authors and Affiliations

  1. Laboratory of Molecular Iron Metabolism, Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry, and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China

    Shiyang Chang, Peina Wang, Yingying Han, Guofen Gao & Yan-Zhong Chang

  2. College of Basic Medicine, Hebei Medical University, Shijiazhuang, 050017, China

    Shiyang Chang & Peina Wang

  3. State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences (CAS), BNU IDG/McGovern Institute for Brain Research, Beijing, 100101, China

    Shiyang Chang, Qiang Ma, Zeyuan Liu, Yufeng Lu, Ruiguo Chen & Xiaoqun Wang

  4. State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, 100875, China

    Suijuan Zhong & Qian Wu

  5. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China

    Le Sun

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  1. Shiyang Chang
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Chang, S., Wang, P., Han, Y. et al. Ferrodifferentiation regulates neurodevelopment via ROS generation. Sci. China Life Sci. 66, 1841–1857 (2023). https://doi.org/10.1007/s11427-022-2297-y

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