美国哥伦比亚大学欧文医学中心Wellington V. Cardoso、Munemasa Mori与斯坦福大学医学院Hiromitsu Nakauchi等研究人员合作利用多能干细胞构，通过条件性囊胚互补建出具有功能的肺。2019年11月7日，《自然—医学》在线发表了该研究成果。

通过条件性囊胚互补（CBC）方法，研究人员在小鼠中成功构建出具有功能的肺，该方法可在嵌合宿主中的腾出特定微环境，从而让供体小鼠的多能干细胞（PSC）实现器官生成。研究人员发现，野生型供体PSC拯救了遗传缺陷受体小鼠胚胎中的肺部形成，在这些缺陷模型小鼠中早期呼吸内胚层祖细胞无法分化（由于Ctnnb1^cnull突变）或扩增（由于Fgfr2^cnull突变）。被拯救的新生小鼠可存活至成年，其肺功能与野生型同窝仔的肺功能无可见差别。有效的嵌合体形成和肺部互补需要近期研发的培养条件，以保持供体PSC的发育潜力，并与整体DNA甲基化不足和H4组蛋白乙酰化增加有关。这些结果为在大型动物中产生肺部的新策略铺平了道路，从而使人肺部疾病以及基于细胞的治疗性干预成为可能。

据了解，由于治疗选择不足和肺移植供体器官的可用性有限，全世界数百万患有无法治愈的晚期肺疾病的人死亡。当前使肺再生的生物工程策略无法复制其非凡的细胞多样性和复杂的三维排列，这些结构对于维持生命的气体交换是必不可少的。

附：英文原文

Title: Generation of functional lungs via conditional blastocyst complementation using pluripotent stem cells

Author: Munemasa Mori, Kazuhiro Furuhashi, Jennifer A. Danielsson, Yuichi Hirata, Miwako Kakiuchi, Chyuan-Sheng Lin, Mayu Ohta, Paul Riccio, Yusuke Takahashi, Xinjing Xu, Charles W. Emala, Chao Lu, Hiromitsu Nakauchi, Wellington V. Cardoso

Issue&Volume: 2019-11-07

Abstract: Millions of people worldwide with incurable end-stage lung disease die because of inadequate treatment options and limited availability of donor organs for lung transplantation1. Current bioengineering strategies to regenerate the lung have not been able to replicate its extraordinary cellular diversity and complex three-dimensional arrangement, which are indispensable for life-sustaining gas exchange2,3. Here we report the successful generation of functional lungs in mice through a conditional blastocyst complementation (CBC) approach that vacates a specific niche in chimeric hosts and allows for initiation of organogenesis by donor mouse pluripotent stem cells (PSCs). We show that wild-type donor PSCs rescued lung formation in genetically defective recipient mouse embryos unable to specify (due to Ctnnb1cnull mutation) or expand (due to Fgfr2cnull mutation) early respiratory endodermal progenitors. Rescued neonates survived into adulthood and had lungs functionally indistinguishable from those of wild-type littermates. Efficient chimera formation and lung complementation required newly developed culture conditions that maintained the developmental potential of the donor PSCs and were associated with global DNA hypomethylation and increased H4 histone acetylation. These results pave the way for the development of new strategies for generating lungs in large animals to enable modeling of human lung disease as well as cell-based therapeutic interventions46. Pluripotent stem cells can generate functional lungs when injected into blastocyst-stage mouse embryos, a step toward the goal of growing human lungs in large animals for disease modeling and therapeutic applications.

DOI: 10.1038/s41591-019-0635-8

Source: https://www.nature.com/articles/s41591-019-0635-8