Fast generation of forebrain oligodendrocyte spheroids from human embryonic stem cells by transcription factors

Ling Ma; Yuting Mei; Peibo Xu; Yan Cheng; Zhiwen You; Xiaoli Ji; Deyi Zhuang; Wenhao Zhou; Yuejun Chen; Man Xiong

doi:10.1016/j.isci.2022.105172

Fast generation of forebrain oligodendrocyte spheroids from human embryonic stem cells by transcription factors

iScience. 2022 Sep 20;25(10):105172. doi: 10.1016/j.isci.2022.105172. eCollection 2022 Oct 21.

Authors

Ling Ma¹, Yuting Mei¹, Peibo Xu², Yan Cheng¹, Zhiwen You², Xiaoli Ji³, Deyi Zhuang⁴, Wenhao Zhou^{3

5}, Yuejun Chen², Man Xiong⁵

Affiliations

¹ Stem Cell Center of Children's Hospital, Fudan University, Shanghai 201102, China.
² Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
³ Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China.
⁴ Fujian Key Laboratory of Neonatal Diseases, Xiamen Key Laboratory of Neonatal Diseases, Xiamen Children's Hospital, Xiamen 361006, China.
⁵ State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.

Abstract

Oligodendrocyte spheroids (OL-spheroids) containing oligodendrocytes and neurons provide an accessible system to dissect demyelinating diseases and test therapeutic treatment. However, generation of human OL-spheroids is still technically challenging and time-consuming until now. Here, we presented evidence that overexpression of SOX10 and OLIG2 (SO) in human embryonic stem cells (hESCs)-derived ventral forebrain neural progenitors is sufficient to produce forebrain pre-oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) within 20-40 days. More importantly, optimizing this procedure by overexpression of SO in ventral forebrain spheroids, we successfully generated OL-spheroids with pre-OLs, mature OLs, and neurons 40 days after OL-induction. We further demonstrated oligodendrocyte-neuron interactions and obvious axon myelination in OL-spheroids. Finally, over 30% cells developed into mature oligodendrocytes with forebrain identity and myelinate axons in mouse brain 3 months after transplantation. This study provides a strategy to generate forebrain OL-spheroids rapidly and efficiently which would facilitate development of new therapeutics for demyelinating disorders.

Keywords: Biological sciences; Biotechnology; Cell biology; Cellular neuroscience; Stem cells research.