Transcriptional Regulation of Lung Alveolar Regeneration

摘要 呼吸系统由多个独特的、空间上不同的隔室组成，这些隔间对 损伤和疾病的状态根据它们的细胞和细胞外成分而不同。牙槽骨 隔室或壁龛负责与外部环境的大部分气体交换 肺，是一个在慢性阻塞性肺疾病期间发生显著变化的区域 疾病(COPD)和特发性肺纤维化(IPF)。在肺泡内，至少有两个主要的 成熟上皮细胞类型，肺泡1型(AT1)和肺泡2型(AT2)，以及各种 间充质细胞包括PDGFRA+/Axin2+间充质肺泡龛细胞(Mancs)、Axin2+ 肌成纤维细胞前体细胞(AMPs)，以及定义不清的血管内皮细胞群。尽管我们 随着对构成肺泡的细胞类型的了解不断增加，我们对它们是如何形成的知之甚少 相互交流或他们的祖先分化的后代关系最终是如何 受监管的。为了解决这些问题，我们建议描述成熟成人的遗传途径。 以更好地了解肺内稳态和肺内环境的转录和表观遗传机制 再生。我们的初步数据已经确定了两个新的和重要的肺泡转录调节因子 上皮的动态平衡和再生：Tfcp2l1和Klf5。我们的初步数据表明，Tfcp2l1和Klf5 以相反的方式调控AEP和AT2细胞的自我更新及其向AT1细胞的分化。 Tfcp2l1是限制AT2分化为AT1血统所必需的，而Klf5是许可所必需的 急性损伤后AT2细胞分化为AT1细胞的能力。此外，我们的初步数据表明 Tfcp2l1标记AEP亚系的方式类似于Lgr5标记肠道干细胞的方式。 总而言之，这些数据提供了对肺泡分子和细胞协调的重要洞察力 通过参与细胞类型特定的转录途径来实现动态平衡和再生 调节上皮细胞系的自我更新和分化。

ABSTRACT The respiratory system is comprised of multiple unique and spatially distinct compartments that respond to injury and diseases states differently based on their cellular and extracellular composition. The alveolar compartment or niche is responsible for the majority of gas exchange with the external environment in the lungs and is an area that is dramatically altered during lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Within the alveolus, there are at least two major mature epithelial cell types, alveolar type 1 (AT1) and alveolar type 2 cells (AT2), as well as various mesenchymal cells including Pdgfra+/Axin2+ mesenchymal alveolar niche cells (MANCs), Axin2+ myofibroblast precursor cells (AMPs), and poorly defined vascular endothelial cell populations. Despite our increasing knowledge of the cell types that comprise the lung alveolus, we have little information on how they communicate with each other or how their progenitor-differentiated progeny relationships are ultimately regulated. To address these questions, we propose to characterize the genetic pathways of the mature adult lung to better understand the transcriptional and epigenetic mechanisms underlying lung homeostasis and regeneration. Our preliminary data has identified two new and important transcriptional regulators of alveolar epithelial homeostasis and regeneration: Tfcp2l1 and Klf5. Our preliminary data suggest that Tfcp2l1 and Klf5 regulate the self-renewal of AEP and AT2 cells and their differentiation into AT1 cells, in opposing manners. Tfcp2l1 is essential in restricting AT2 differentiation into the AT1 lineage whereas Klf5 is essential for licensing the ability of AT2 cells to differentiate into AT1 cells after acute injury. Moreover, our preliminary data suggests that Tfcp2l1 marks the AEP sublineage in a manner similar to how Lgr5 marks the intestinal stem cell. Together, these data provide critical insight into the molecular and cellular orchestration of alveolar homeostasis and regeneration through the engagement of cell type specific transcriptional pathways that regulate self-renewal and differentiation of epithelial cell lineages.