ICNC Abstracts, ICNC 2018

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Modeling vanishing white matter disease with patient-derived induced pluripotent stem cell reveals astrocytic dysfunction
Ling Zhou, Peng Li, Na Chen, Lifang Dai, Yinan Liu, Li Shen, Jingmin Wang, Yuwu Jiang, Ye Wu

Last modified: 2018-09-09

Abstract


Purpose

Vanishing white matter disease (VWM) is one of the most prevalent inherited leukoencephalopathies in children. Although the defects are in the housekeeping genes EIF2B1–5, VWM is primarily a leukoencephalopathy. No model for VWM induced pluripotent cells (iPSCs) has been established for exploring the mechanism of VWM.

Materials and Methods

2 VWM iPSCs model was established by a virus-free nonintegrating episomal system. Wild-type and VWM iPSCs were sequentially differentiated into neural stem cells (NSCs), then into neurons, oligodendrocytes and astrocytes. Apoptosis was detected by Annexin V/PI.

Results

(1) Two VWM iPSCs models were successfully established and identified: alkaline phosphatase staining was positive and iPSCs expressed pluripotent markers NANOG and SSEA4. Moreover, teratoma assay showed that iPSCs have potential of differentiation into three germ layers. (2) Wild-type and VWM iPSCs derived NSCs can differentiated into neurons and oligodendrocytes. (3) VWM iPSCs derived astrocytes revealed dysfunction. 1) VWM iPSC-derived astrocytes were dysmorphic, manifested as shorter processes. 2) Total GFAP and α GFAP of VWM astrocytes were fewer than wild-type in mRNA level, whereas δ GFAP was much higher. 3) The early and total apoptosis rates of wild-type, VWM1, and VWM2 astrocytes were higher than those of the wild-type astrocytes, p<0.05.

Conclusion

The establishment of VWM-specific iPSC models provides a platform for exploring the pathogenesis of VWM and future drug screening. The results suggested that in vitro differentiation of wild-type and VWM iPSCs into NSCs, neurons, and OLs showed no significant difference. Whereas, VWM astrocytes exhibited abnormal morphology and dysfunction.


Keywords


vanishing white matter disease (VWM), induced pluripotent stem cells (iPSCs), neural stem cells (NSCs), oligodendrocytes, astrocytes

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