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.

摘要 典型地，肺泡组织是静止的，具有最小的细胞更新，然而， 细胞（AT 2）保持兼性再生能力。称为肺泡上皮细胞的AT 2细胞亚群 祖细胞（AEP）是Wnt应答性的，表达Wnt靶基因Axin 2，并有助于增强肺泡巨噬细胞的功能。 再生鉴于慢性下呼吸道疾病，包括慢性阻塞性肺病、慢性支气管炎、肺气肿 和哮喘，现在是美国第三大死亡原因，肺的修复能力仅次于 受伤对生存至关重要。哺乳动物的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合理设计是必要的 再生疗法复杂肺组织的各个组成部分必须共同工作， 保持足够的气体交换和屏障功能。重要的是，刺激内源性 再生将比目前用于器官衰竭的治疗选择侵入性更小并且更经济。 肺泡的兼性干细胞在发育过程中被预先定义的程度， 在成年期保持是模糊的。如果AT 2细胞的子集（例如AEP）以独特的细胞因子维持， 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，鉴于 AEP的兼性性质，这些基因调控状态应该在发育过程中定义， 在整个成熟过程中保持。 整合可用的RNA-seq、ATAC-seq和全肺scRNA-seq数据，我确定了一组推定的 AEP特异性转录因子，包括禾谷类/CP 2家族转录因子Tfcp 211。的 Tfcp 2l 1基因先前被证明是Wnt反应性的，因此可以标记AEP亚系。 类似于Axin 2。重要的是，已知Tfcp 2l 1抑制小鼠ES细胞中的谱系定型 提示它可能在维持AEP的多能状态中发挥功能性作用。因此，本提案旨在 了解一个特定的转录因子在肺发育和再生中的作用。通过 理解AT 2/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。