Human-induced pluripotent stem cell-derived cerebral organoid of leukoencephalopathy with vanishing white matter

IntroductionLeukoencephalopathy with vanishing white matter (VWM) is a rare autosomal recessive leukoencephalopathy resulting from mutations in EIF2B1-5, which encode subunits of eukaryotic translation initiation factor 2B (eIF2B). Studies have found that eIF2B mutation has a certain influence on embryonic brain development. So far, the effect of the eIF2B mutations on the dynamic process of brain development is not fully understood yet. AimsThree-dimensional brain organoid technology has promoted the study of human nervous system developmental diseases in recent years, providing a potential platform for elucidating the pathological mechanism of neurodevelopmental diseases. In this study, we aimed to investigate the effects of eIF2B mutation on the differentiation and development of different nerve cells during dynamic brain development process using 3D brain organoids. ResultsWe constructed eIF2B mutant and wild-type brain organoid model with induced pluripotent stem cell (iPSC). Compared with the wild type, the mutant brain organoids were significantly smaller, accompanied by increase in apoptosis, which might be resulted from overactivation of unfolded protein response (UPR). Neuronal development was delayed in early stage, but with normal superficial neuronal differentiation in later stage. eIF2B mutations resulted in immature astrocytes with increased expression of GFAP delta, nestin, and alpha B-crystallin, and there were increased oligodendrocyte progenitor cells, decreased mature oligodendrocytes, and sparse myelin in mutant cerebral organoids in the later stage. Conclusionwe constructed the first eIF2B mutant cerebral organoids to explore the dynamic brain development process, which provides a platform for further research on the specific pathogenesis of VWM.

Automated summary

This study investigated the effects of eIF2B mutation on the differentiation and development of different nerve cells during the dynamic brain development process using 3D brain organoids. The mutant brain organoids were smaller and showed increased apoptosis. Neuronal development was delayed in the early stage, but superficial neuronal differentiation was normal in the later stage. The mutant organoids had immature astrocytes, increased oligodendrocyte progenitor cells, decreased mature oligodendrocytes, and sparse myelin. These findings provide a platform for further research on the specific pathogenesis of VWM.