Abstract
Mutations in STAMBP have been well-established to cause congenital human microcephaly-capillary malformation (MIC-CAP) syndrome, a rare genetic disorder characterized by global developmental delay, severe microcephaly, capillary malformations, etc. Previous biochemical investigations and loss-of-function studies in mice have provided insights into the mechanism of STAMBP, however, it remains controversial how STAMBP deficiency leads to malformation of those affected tissues in patients. In this study, we investigated the function and underlying mechanism of STAMBP during neural differentiation of human embryonic stem cells (hESCs). We found that STAMBP is dispensable for the pluripotency maintenance or neural differentiation of hESCs. However, neural progenitor cells (NPCs) derived from STAMBP-deficient hESCs fail to be long-term maintained/expanded in vitro. We identified the anti-apoptotic protein CFLAR is down-regulated in those affected NPCs and ectopic expression of CFLAR rescues NPC defects induced by STAMBP-deficiency. Our study not only provides novel insight into the mechanism of neural defects in STAMBP mutant patients, it also indicates that the death receptor mediated apoptosis is an obstacle for long-term maintenance/expansion of NPCs in vitro thus counteracting this cell death pathway could be beneficial to the generation of NPCs in vitro.
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Data Availability
RNA-Seq data are available at the NCBI Gene Expression Omnibus database (GEO: GSE245689). Materials and additional details can be made available by the corresponding author upon reasonable request.
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Acknowledgements
The authors thank lab members in GIBH and CityU for their kind help.
Funding
This work was partially supported by the Basic Research Project of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (GIBHBRP23-02) and the Science and Technology Planning Project of Guangdong Province (2023B1212060050, 2023B1212120009).
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X.S. and J.Z. initiated and designed the project, and wrote the manuscript. J.Z. and Y.Z. performed most experiments and analyzed results. Y.L. helped RNA-Seq analysis. T.Z. performed the karyotype analysis of KO and WT hESCs. J.H. and G.P. provided resources. All authors read and approved the final manuscript.
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Zhang, J., Zhang, Y., Liu, Y. et al. STAMBP is Required for Long-Term Maintenance of Neural Progenitor Cells Derived from hESCs. Stem Cell Rev and Rep (2024). https://doi.org/10.1007/s12015-024-10751-1
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DOI: https://doi.org/10.1007/s12015-024-10751-1