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Secretomics Alterations and Astrocyte Dysfunction in Human iPSC of Leukoencephalopathy with Vanishing White Matter

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Abstract

Leukoencephalopathy with vanishing white matter (VWM) is an inherited leukoencephalopathy characterized by progressive rarefaction of cerebral white matter. Dysfunction of patient astrocyte plays a central role in the pathogenesis, while the immaturity of oligodendrocyte is probably secondary. How eIF2B mutant astrocytes affect the maturation and myelination of oligodendrocyte precursor cells (OPCs) is unclear yet. We used induced pluripotent stem cells (iPSCs) derived from our patient with EIF2B5 mutations to differentiate into astrocytes (AS) and OPCs, and aimed to verify that patient astrocytes inhibited the differentiation of OPCs by abnormalities of secreted proteins. eIF2B mutant astrocytes and astrocyte-conditioned medium (ACM) both inhibited the maturation of OPCs. It was revealed that 13 promising proteins exhibited a similar up- or downregulation by the PRM method correlated well with TMT results. eIF2B mutant astrocytes may secrete abnormal extracellular matrix (HA, LAMA4, BGN, FBN1, VASN, PCOLCE, MFAP4), cytokines (IL-6, CRABP1, ISG15), growth factors (PDGF-AA, CNTF, IGF-II, sFRP1, SERPINF1) and increased FABP7, which might lead to the differentiation and maturation disorder of OPCs. We analyzed the astrocyte-conditioned medium to find the key secretory molecules affecting the differentiation and maturation of OPCs, which provides potential clues for further research on the mechanism of VWM.

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The original contributions presented in the study are included in the article and supplementary material, further inquiries can be directed to the corresponding author on reasonable request.

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Funding

This research was supported by the Program of the Natural Science Foundation of China (Grant Number [82171694] and [81901155]), and Beijing Natural Science Foundation (Grant Number [L202034]).

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Authors and Affiliations

  1. Department of Pediatrics, Peking University First Hospital, Beijing, China

    Jiong Deng, Jie Zhang, Kai Gao, Wei Yan, Ling Zhou, Yuwu Jiang, Jingmin Wang & Ye Wu

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  1. Jiong Deng
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  2. Jie Zhang
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  3. Kai Gao
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  4. Wei Yan
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  5. Ling Zhou
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  6. Yuwu Jiang
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  7. Jingmin Wang
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  8. Ye Wu
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JD, JZ and YW. The first draft of the manuscript was written by JD and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ye Wu.

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Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Medical Ethics Committee of Peking University First Hospital (2022[176]).

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The written informed consent was obtained from the parents.

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Deng, J., Zhang, J., Gao, K. et al. Secretomics Alterations and Astrocyte Dysfunction in Human iPSC of Leukoencephalopathy with Vanishing White Matter. Neurochem Res 47, 3747–3760 (2022). https://doi.org/10.1007/s11064-022-03765-z

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