Mapping the genetic and cellular regulatory landscape of lung epithelial regeneration

摘要 典型地，肺泡组织是静止的，细胞周转最少，然而，上皮肺泡2型。 细胞(AT2)保持兼性再生能力。称为肺泡上皮的AT2细胞亚群 祖细胞(AEP)对WNT有反应，表达WNT靶基因Axin2，并促进肺泡发育 再生。鉴于慢性下呼吸道疾病包括COPD、慢性支气管炎、肺气肿 和哮喘，现在是美国的第三大死因，肺的修复能力仅次于 受伤是生存的首要条件。哺乳动物的肺表现出广泛的修复能力和 了解肺的不同组织可以修复的程度是合理设计所必需的 再生疗法。复杂肺组织的各个组成部分必须协同工作才能 保持足够的气体交换和屏障功能。重要的是，内源性刺激 再生将比目前器官衰竭的治疗方案侵入性更小，更经济。 肺泡兼性干细胞在发育和发育过程中预先定义的程度 在成年期间维持的是模棱两可的。如果诸如AEP之类的AT2小区的子集被维护为唯一的 再生特性，那么这些细胞应该由不同的基因调控状态来定义。表面上，给出了 AEP的兼性，这些基因调节状态应该在发育过程中定义和 在整个成熟过程中一直保持。 整合现有的rna-seq、atac-seq和全肺scRNA-seq数据，我确定了一组可能的 AEP特异的转录因子，包括Grainyhead/CP2家族转录因子Tfcp2l1。这个 Tfcp2l1基因以前被证明是Wnt反应的，因此可以标记AEP亚型 类似于Axin2的时尚。重要的是，已知Tfcp2l1可以抑制小鼠ES细胞的谱系承诺 提示它可能在维持AEP的多潜能状态中发挥作用。因此，这项建议旨在 了解特定转录因子在肺发育和再生中的作用。通过 认识AT2/AEP兼性干细胞状态的遗传控制合理设计操作方法 或提高这些细胞的再生能力都可以得到开发。

Abstract Typically, lung alveolar tissue is quiescent with minimal cellular turnover, however, epithelial alveolar type 2 cells (AT2) maintain a facultative regenerative capacity. A subset of AT2 cells termed alveolar epithelial progenitors (AEPs) are Wnt responsive, express the Wnt target gene Axin2, and contribute to robust alveolar regeneration. Given that chronic lower respiratory disease including COPD, chronic bronchitis, emphysema and asthma, is now the third leading cause of death in the United states, the ability of the lung to repair after injury is paramount to survival. The mammalian lung exhibits a broad range of reparative capabilities and understanding the degree to which different tissues of the lung can repair is necessary for the rational design of regenerative therapies. The individual components of the complex lung tissue must work together to maintain both adequate gas exchange and barrier function. Importantly, stimulation of endogenous regeneration would be less invasive and more economical than current treatment options for organ failure. The extent to which the facultative stem cells of the lung alveolus are pre-defined during development and maintained during adulthood is ambiguous. If subsets of AT2 cells such as AEPs are maintained with unique regenerative properties, then these cells should be defined by distinct gene regulatory states. Ostensibly, given the facultative nature of AEPs, these gene regulatory states should be developmentally defined and maintained throughout maturation. Integrating available RNA-seq, ATAC-seq and whole lung scRNA-seq data, I identified a putative set of transcription factors specific to AEPs including the grainyhead/CP2 family transcription factor Tfcp2l1. The Tfcp2l1 gene was previously shown to be Wnt responsive and thus could mark the AEP sublineage in a fashion similar to Axin2. Importantly, Tfcp2l1 is known to repress lineage commitment in mouse ES cells suggesting it could play a functional role in maintaining the multipotent state of AEPs. Thus, this proposal aims to understand the role of a specific transcription factor in lung development and regeneration. By understanding genetic control of AT2/AEP facultative stem cell state rationally designed methods to manipulate or improve regenerative ability of these cells can be developed.