Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung
- Columbia University Medical Center, United States
- Boston University, United States
- Icahn School of Medicine at Mount Sinai, United States
- University of Washington, United States
- Okayama University, Japan
- The University of Texas Southwestern Medical Center, United States
- Columbia University, United States
Abstract
Millions suffer from incurable lung diseases, and the donor lung shortage hampers organ transplants. Generating the whole organ in conjunction with the thymus is a significant milestone for organ transplantation because the thymus is the central organ to educate immune cells. Using lineage-tracing mice and human pluripotent stem cell (PSC)-derived lung-directed differentiation, we revealed that gastrulating Foxa2 lineage contributed to both lung mesenchyme and epithelium formation. Interestingly, Foxa2 lineage-derived cells in the lung mesenchyme progressively increased and occupied more than half of the mesenchyme niche, including endothelial cells, during lung development. Foxa2 promoter-driven, conditional Fgfr2 gene depletion caused the lung and thymus agenesis phenotype in mice. Wild-type donor mouse PSCs injected into their blastocysts rescued this phenotype by complementing the Fgfr2-defective niche in the lung epithelium and mesenchyme and thymic epithelium. Donor cell is shown to replace the entire lung epithelial and robust mesenchymal niche during lung development, efficiently complementing the nearly entire lung niche. Importantly, those mice survived until adulthood with normal lung function. These results suggest that our Foxa2 lineage-based model is unique for the progressive mobilization of donor cells into both epithelial and mesenchymal lung niches and thymus generation, which can provide critical insights into studying lung transplantation post-transplantation shortly.
Data availability
scRNA-seq data for mouse gastrulation and early organogenesis described in the manuscript have been analyzed from the deposited database athttps://marionilab.cruk.cam.ac.uk/MouseGastrulation2018/. The authors declare that all data supporting the results of this study are available within the paper and the Supplementary
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Funding
NHLBI Division of Intramural Research (1R01 HL148223-01)
- Munemasa Mori
U.S. Department of Defense (PR190557)
- Munemasa Mori
U.S. Department of Defense (PR191133)
- Munemasa Mori
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by Columbia University Institutional Animal Care and Use Committee protocols (AABF8554) in accordance with US National Institutes of Health guidelines.
Human subjects: All works using human iPSC lines are derived from deidentified materials here were conducted under the approval of the ethical committee meeting at Columbia University Medical Canter without the requirement of IRB.
Copyright
© 2023, Miura et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung
eLife 12:e86105.
https://doi.org/10.7554/eLife.86105
