Molecular pathways controlling alveolar epithelial remodeling in development and regeneration

摘要 肺泡的形成是呼吸系统发育过程中的最高事件。的 肺泡执行呼吸系统的标志性功能：心血管系统之间的气体交换。 制度和外部环境。小鼠的肺泡形成大约在出生时开始，在2-4岁之间结束， 小鼠出生后的寿命为几周，但人类出生后可延长数年。肺泡发生中断 可导致严重的儿科疾病，如支气管肺发育不良（BPD）， 肺泡内环境的再生或持续退化可导致慢性阻塞性肺疾病 疾病（COPD）。成熟的肺泡含有大量的上皮细胞、内皮细胞和间充质细胞 血统，所有这些都必须适当地沟通，以形成一个有效交流的功能性生态位 气体与外部环境。尽管肺泡很重要，但我们仍然几乎没有 信息如何在肺泡内的各种细胞谱系相互沟通， 肺泡发育或再生。在上一个资助期内，我们已确定 许多新的转录、表观遗传和信号传导途径在发育中发挥重要作用， 体内平衡和肺泡再生。我们在第一次会议期间也作出了广泛的努力， 在单细胞水平上定义完整的细胞库，分子通路，发育 轨迹，细胞可塑性和瞬时细胞表型，在肺泡发生过程中存在，以获得一个 更好地了解肺发育的这一关键阶段及其对损伤的反应。这些初步 数据已经证实了我们先前的工作，显示了TGF-β等途径的重要性，并开始 定义驱动发展和成熟的分子线索知之甚少的细胞谱系，包括 肺泡1型（AT 1）细胞。总之，我们的数据揭示了两个新的见解AT 1细胞生物学：1）AT 1细胞 在发育和成熟的肺泡和2）AT 1细胞中，在介导细胞串扰中发挥核心作用，但 而不是AT 2细胞，在新生儿损伤中表现出显着的谱系可塑性水平，这种可塑性是 在某种程度上是由河马途径控制的。总之，我们的研究强调了AT 1细胞在 肺泡发育和体内平衡。

ABSTRACT The formation of the lung alveolus is the culminative event in the development of the respiratory system. The alveoli perform the hallmark function of the respiratory system: gas exchange between the cardiovascular system and the external environment. Alveologenesis begins at approximately birth in mice, ends between 2-4 weeks of postnatal life in mice but extends several years after birth in humans. Disruptions in alveologenesis can lead to severe pediatric diseases such as bronchopulmonary dysplasia (BPD), and in the adult, defective regeneration or persistent degeneration of alveolar homeostasis can lead to chronic obstructive pulmonary disease (COPD). The mature lung alveolus contains a myriad of epithelial, endothelial, and mesenchymal cell lineages, all of which have to communicate properly to form a functional niche that efficiently exchanges gasses with the external environment. Despite the importance of the lung alveolus, we still have little information how the multifarious cell lineages within the lung alveolus communicate with each other during alveolar development or regeneration. During the previous funding period of this grant, we have identified many novel transcriptional, epigenetic, and signaling pathways that play essential roles in the development, homeostasis, and regeneration of the lung alveolus. We have also dedicated extensive effort during the first funding period in defining at a single cell level the full cellular repertoire, molecular pathways, developmental trajectories, cellular plasticity, and transient cell phenotypes that are present during alveologenesis, to derive a better understanding of this critical stage of lung development and its response to injury. These preliminary data have confirmed our previous work showing the importance of pathways such as Tgf-beta, and begun to define the molecular cues that drive development and maturation of poorly understood cell lineages including the alveolar type 1 (AT1) cell. Together, our data reveal two novel insights into AT1 cell biology: 1) AT1 cells play a central role in mediating cellular crosstalk in the developing and mature alveolus and 2) AT1 cells, but not AT2 cells, exhibit a remarkable level of lineage plasticity in response to neonatal injury and this plasticity is controlled, in part, by the Hippo pathway. Taken together, our studies highlight the central role AT1 cells play in alveolar development and homeostasis.