Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes generation of the whole lung
Conditional blastocyst complementation of a defective Foxa2 lineage efficiently promotes generation of the whole lung
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有条件的囊胚互补有缺陷的 Foxa2 谱系可有效促进整个肺的生成
DOI：
10.1101/2022.10.31.514628
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Mori Munemasa
中科院分区：
文献类型：
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作者：
Miura Akihiro;Sarmah Hemanta;Tanaka Junichi;Hwang Youngmin;Sawada Anri;Shimamura Yuko;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
数百万人患有无法治愈的肺病，而供体肺的短缺阻碍了器官移植。与胸腺一起产生整个器官是器官移植的一个重要里程碑，因为胸腺是培养免疫细胞的中心器官。通过对小鼠和人类多能干细胞（PSC）衍生的肺定向分化进行谱系追踪，我们发现原肠胚Foxa2谱系有助于肺间质和上皮的形成。有趣的是，在肺发育过程中，肺间质中Foxa2谱系来源的细胞逐渐增加，并占据了超过一半的间质生态位，包括内皮细胞。Foxa2启动子驱动的条件性Fgfr2基因缺失导致小鼠肺和胸腺发育不全表型。将野生型供体小鼠PSCs注射到囊胚中，通过补充肺上皮、间充质和胸腺上皮中fgfr2缺陷的生态位，挽救了这种表型。在肺发育过程中，供体细胞取代了整个肺上皮和强大的间充质生态位，有效地补充了几乎整个肺生态位。重要的是，这些小鼠存活到成年，肺功能正常。这些结果表明，我们基于Foxa2谱系的模型对于供体细胞逐渐动员到上皮和间充质肺壁龛和胸腺生成是独一无二的，这可以为移植后肺移植的研究提供重要的见解。
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.