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Foxa1 disruption enhances human cell integration in human-mouse interspecies chimeras
Li-Na Wang1,2,3, Jun-Shuang Jia1,3, Xing-Long Yang4
1Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
Cell and Tissue Research
|December 21, 2024
Summary
Foxa1 gene disruption in mouse embryos creates a niche for human cell integration, advancing humanized rodent models for Epstein-Barr virus research. Further work is needed to overcome embryonic lethality.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Virology
Background:
- Generating rodent models with humanized nasopharyngeal epithelium (NE) is crucial for studying Epstein-Barr virus (EBV) and nasopharyngeal carcinoma.
- Specific gene knockouts needed to create a developmental niche for NE in blastocyst complementation models are not fully understood.
- Foxa1's role in NE development requires further investigation for its potential in creating such a niche.
Purpose of the Study:
- To investigate if Foxa1 disruption can create a developmental niche for human nasopharyngeal epithelium (NE) in mouse embryos.
- To assess the integration and proliferation of human pluripotent stem cells (hPSCs) in Foxa1-deficient mouse embryos using blastocyst complementation.
- To evaluate the potential of Foxa1-deficient mouse embryos for generating humanized NE for EBV studies.
Main Methods:
- Bioinformatics analysis of Foxa1 expression patterns during mouse embryonic development.
- Generation of Foxa1 mutant mice and MYD88-inactivated hPSCs.
- Blastocyst complementation assay using Foxa1-deficient and control mouse blastocysts with hPSCs, followed by chimerism evaluation via PCR and immunohistochemistry.
Main Results:
- Bioinformatics and mutant mouse studies indicated Foxa1's critical role in NE development and suggested its disruption could create a developmental niche.
- Human cells integrated into 80% of Foxa1-deficient embryos, showing robust proliferation, significantly higher than controls (4.17%).
- Chimeras derived from Foxa1-deficient embryos exhibited embryonic lethality, surviving only up to E10.5, hindering further evaluation of humanized NE.
Conclusions:
- Foxa1 disruption significantly enhances human cell integration in human-mouse interspecies chimeras, facilitating the generation of endoderm-derived organs.
- Overcoming embryonic lethality in Foxa1-deficient chimeras is essential for successfully generating humanized NE.
- This study provides a foundation for developing humanized NE models for EBV and nasopharyngeal carcinoma research.
