Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland; University of Basel, Basel, Switzerland; Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
Dev Cell. 2020 Apr 6;53(1):117-128.e6. doi: 10.1016/j.devcel.2020.01.033. Epub 2020 Feb 27.
Bud tip progenitor cells give rise to all murine lung epithelial lineages and have been described in the developing human lung; however, the mechanisms controlling human bud tip differentiation into specific lineages are unclear. Here, we used homogeneous human bud tip organoid cultures and identified SMAD signaling as a key regulator of the bud tip-to-airway transition. SMAD induction led to the differentiation of airway-like organoids possessing functional basal cells capable of clonal expansion and multilineage differentiation. To benchmark in vitro-derived organoids, we developed a single-cell mRNA sequencing atlas of the human lung from 11.5 to 21 weeks of development, which revealed high degrees of similarity between the in vitro-derived and in vivo airway. Together, this work sheds light on human airway differentiation in vitro and provides a single-cell atlas of the developing human lung.
芽尖祖细胞产生所有的鼠类肺上皮谱系，在发育中的人类肺中也有描述；然而，控制人类芽尖分化为特定谱系的机制尚不清楚。在这里，我们使用同质的人类芽尖类器官培养物，并鉴定出 SMAD 信号作为芽尖向气道过渡的关键调节因子。SMAD 的诱导导致具有功能性基底细胞的气道样类器官的分化，这些基底细胞能够克隆扩增和多谱系分化。为了对体外衍生的类器官进行基准测试，我们从 11.5 周到 21 周的发育过程中，开发了一个人类肺的单细胞 mRNA 测序图谱，该图谱显示了体外衍生的和体内气道之间具有高度的相似性。总之，这项工作阐明了体外人类气道分化的机制，并提供了一个发育中人类肺的单细胞图谱。
