Molecular pathways controlling alveolar epithelial remodeling in development and regeneration

摘要 肺泡的形成是呼吸系统发育的终极事件。这个 肺泡执行呼吸系统的标志性功能：心血管之间的气体交换 系统和外部环境。小鼠的肺泡发生大约在出生时开始，在2-4岁之间结束 小鼠的出生后寿命为数周，但人类出生后的寿命可延长数年。肺泡发育的中断 可导致严重的儿科疾病，如支气管肺发育不良(BPD)，在成人中， 肺泡稳态再生或持续退化可导致慢性阻塞性肺 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，所有这些都必须正确地沟通，以形成一个有效地交换的功能利基 与外部环境产生气体。尽管肺泡很重要，但我们仍然很少 肺泡内不同细胞系如何相互沟通的信息 肺泡发育或再生。在这笔赠款的上一个资助期内，我们已经确定 许多新的转录、表观遗传和信号通路在发育中发挥重要作用， 动态平衡和肺泡再生。我们还在第一个阶段投入了大量的努力 在单个细胞水平上定义完整的细胞谱、分子途径、发育的资助期 在肺泡形成过程中存在的轨迹、细胞可塑性和瞬时细胞表型，以推导出 更好地了解肺发育的这一关键阶段及其对损伤的反应。这些初步的 数据证实了我们之前的工作，表明了转化生长因子-β等通路的重要性，并开始 定义推动鲜为人知的细胞系发育和成熟的分子线索，包括 肺泡I型(AT1)细胞。总之，我们的数据揭示了对AT1细胞生物学的两个新见解：1)AT1细胞 在发育和成熟的肺泡和AT1细胞中起核心作用，但 而不是AT2细胞，在对新生儿损伤的反应中表现出显著的谱系可塑性，这种可塑性是 这在一定程度上受河马途径的控制。综上所述，我们的研究强调了AT1细胞在 肺泡发育和动态平衡。

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.