Early lineage specification defines alveolar epithelial ontogeny in the murine lung
Early lineage specification defines alveolar epithelial ontogeny in the murine lung
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DOI：
10.1073/pnas.1813952116
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发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Morrisey, Edward E.
中科院分区：
文献类型：
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作者：
Frank, David B.;Penkala, Ian J.;Morrisey, Edward E.
在组织特异性多能祖细胞的逐步特化和分化过程中，谱系特异性转录网络被激活或抑制以协调细胞特化。肺中的气体交换小生境包含两种主要的上皮细胞类型，肺泡1型（AT 1）和AT 2细胞，并且这些细胞的谱系特化的时间对于该小生境的正确形成和出生后存活至关重要。整合细胞特异性谱系追踪研究，空间特异性mRNA转录和蛋白质表达，以及单细胞RNA测序分析，我们证明肺泡上皮细胞命运的规范开始伴随着上皮祖细胞的近端-远端规范和分支形态发生早于以前认识到的。通过使用新开发的双谱系示踪系统，我们表明，双能肺泡细胞，引起AT1和AT2细胞是一个较小的贡献者肺泡上皮细胞群。此外，转录组的单细胞评估在囊泡形成期间鉴定了指定的AT1和AT2祖细胞而不是双能细胞。这些数据揭示了器官形成的范式，其中谱系特化发生在发育的新生阶段，与广泛的组织图案化过程（包括内胚层的轴向图案化和分支形态发生）相一致。
During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal-distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.