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Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung
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 m...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642968/ https://www.ncbi.nlm.nih.gov/pubmed/37861292 http://dx.doi.org/10.7554/eLife.86105 |
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author | Miura, Akihiro Sarmah, Hemanta Tanaka, Junichi Hwang, Youngmin Sawada, Anri Shimamura, Yuko Otoshi, Takehiro Kondo, Yuri Fang, Yinshan Shimizu, Dai Ninish, Zurab Suer, Jake Le Dubois, Nicole C Davis, Jennifer Toyooka, Shinichi Wu, Jun Que, Jianwen Hawkins, Finn J Lin, Chyuan-Sheng Mori, Munemasa |
author_facet | Miura, Akihiro Sarmah, Hemanta Tanaka, Junichi Hwang, Youngmin Sawada, Anri Shimamura, Yuko Otoshi, Takehiro Kondo, Yuri Fang, Yinshan Shimizu, Dai Ninish, Zurab Suer, Jake Le Dubois, Nicole C Davis, Jennifer Toyooka, Shinichi Wu, Jun Que, Jianwen Hawkins, Finn J Lin, Chyuan-Sheng Mori, Munemasa |
author_sort | Miura, Akihiro |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10642968 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-106429682023-11-14 Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung Miura, Akihiro Sarmah, Hemanta Tanaka, Junichi Hwang, Youngmin Sawada, Anri Shimamura, Yuko Otoshi, Takehiro Kondo, Yuri Fang, Yinshan Shimizu, Dai Ninish, Zurab Suer, Jake Le Dubois, Nicole C Davis, Jennifer Toyooka, Shinichi Wu, Jun Que, Jianwen Hawkins, Finn J Lin, Chyuan-Sheng Mori, Munemasa eLife Developmental Biology 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. eLife Sciences Publications, Ltd 2023-10-20 /pmc/articles/PMC10642968/ /pubmed/37861292 http://dx.doi.org/10.7554/eLife.86105 Text en © 2023, Miura et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Developmental Biology Miura, Akihiro Sarmah, Hemanta Tanaka, Junichi Hwang, Youngmin Sawada, Anri Shimamura, Yuko Otoshi, Takehiro Kondo, Yuri Fang, Yinshan Shimizu, Dai Ninish, Zurab Suer, Jake Le Dubois, Nicole C Davis, Jennifer Toyooka, Shinichi Wu, Jun Que, Jianwen Hawkins, Finn J Lin, Chyuan-Sheng Mori, Munemasa Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung |
title | Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung |
title_full | Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung |
title_fullStr | Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung |
title_full_unstemmed | Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung |
title_short | Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes the generation of the whole lung |
title_sort | conditional blastocyst complementation of a defective foxa2 lineage efficiently promotes the generation of the whole lung |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10642968/ https://www.ncbi.nlm.nih.gov/pubmed/37861292 http://dx.doi.org/10.7554/eLife.86105 |
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