Mapping the genetic and cellular regulatory landscape of lung epithelial regeneration

绘制肺上皮再生的遗传和细胞调控图谱

• 批准号: 9911717
• 负责人: John Preston Leach
• 金额: $ 3.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9911717
• 关键词: ATAC-seq; AXIN2 gene; Acute; Address; Adult; Alveolar; Alveolar Cell; Asthma; Biology; Birth; Cause of Death; Cell Lineage; Cells; Chromatin; Chromosome Mapping; Chronic; Chronic Bronchitis; Chronic Obstructive Airway Disease; Complex; Data; Data Set; Defect; Development; Exhibits; Family; Gases; Genes; Genetic; Homeostasis; Individual; Influenza; Injury; Kidney; Knock-out; Knockout Mice; Label; Laboratories; Lung; Lung diseases; Methods; Mus; Natural regeneration; Nature; Neonatal; Organ failure; Phenotype; Physiologic pulse; Play; Process; Property; Publishing; Pulmonary Emphysema; Pulmonary alveolar structure; Regulation; Regulator Genes; Role; Salivary Glands; Specific qualifier value; Structure of parenchyma of lung; Suggestion; Testing; Time; Tissues; United States; Work; alveolar epithelium; cell behavior; conditional knockout; design; embryonic stem cell; epigenome; epithelial stem cell; epithelium regeneration; improved; in vivo; lung development; lung regeneration; postnatal; postnatal development; prevent; progenitor; regenerative; regenerative therapy; repaired; single-cell RNA sequencing; stem cells; surfactant; transcription factor; transcriptome; transcriptome sequencing

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.

抽象的 通常，肺肺泡组织是静止的，细胞周转率最小，但是上皮肺泡2型 细胞（AT2）保持兼职能力。称为肺泡上皮的AT2细胞的子集 祖细胞（AEP）反应迅速，表达Wnt靶基因AXIN2，并有助于稳健的牙槽 再生。鉴于慢性下呼吸道疾病，包括COPD，慢性支气管炎，肺气肿 哮喘和哮喘现在是美国第三大死亡原因，肺部修复后的能力 伤害对于生存至关重要。哺乳动物肺表现出广泛的修复能力， 了解肺的不同组织可以修复的程度对于理性设计是必要的 再生疗法。复杂肺组织的各个成分必须共同起作用 保持足够的气体交换和屏障功能。重要的是，刺激内源性 与当前器官衰竭的当前治疗选择相比，再生的侵入性和经济性更低。 在发育过程中预先定义了肺肺泡的兼性干细胞的程度 在成年期间维持是模棱两可的。如果AT2细胞（例如AEP）的子集保持独特 再生特性，然后这些细胞应由不同的基因调节状态定义。表面上，给予 AEP的兼性性质，这些基因调节状态应在发展上定义，并且 在整个成熟过程中保持。 整合可用的RNA-SEQ，ATAC-SEQ和整个肺Scrna-Seq数据，我确定了一组推定的 特定于AEP的转录因子，包括颗粒状/CP2家族转录因子TFCP2L1。这 先前显示TFCP2L1基因对Wnt的反应敏感，因此可以标记AEP Sublineage A 类似Axin2的时尚。重要的是，已知TFCP2L1在小鼠ES细胞中抑制谱系承诺 表明它可以在维持AEP的多元状态中发挥功能作用。因此，该提议的目的是 了解特定转录因子在肺发育和再生中的作用。经过 了解AT2/AEP辅助干细胞状态合理设计的方法的遗传控制 或可以提高这些细胞的再生能力。