Mapping the genetic and cellular regulatory landscape of lung epithelial regeneration

点击翻译按钮获取中文摘要

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.