Senescence of alveolar epithelial progenitor cells: a critical driver of lung fibrosis

Abstract

Pulmonary fibrosis comprises a range of chronic interstitial lung diseases (ILDs) that impose a significant burden on patients and public health. Among these, idiopathic pulmonary fibrosis (IPF), a disease of aging, is the most common and most severe form of ILD and is treated largely by lung transplantation. The lack of effective treatments to stop or reverse lung fibrosis-in fact, fibrosis in most organs-has sparked the need to understand causative mechanisms with the goal of identifying critical points for potential therapeutic intervention. Findings from many groups have indicated that repeated injury to the alveolar epithelium-where gas exchange occurs-leads to stem cell exhaustion and impaired alveolar repair that, in turn, triggers the onset and progression of fibrosis. Cellular senescence of alveolar epithelial progenitors is a critical cause of stemness failure. Hence, senescence impairs repair and thus contributes significantly to fibrosis. In this review, we discuss recent evidence indicating that senescence of epithelial progenitor cells impairs alveolar homeostasis and repair creating a profibrotic environment. Moreover, we discuss the impact of senescent alveolar epithelial progenitors, alveolar type 2 (AT2) cells, and AT2-derived transitional epithelial cells in fibrosis. Emerging evidence indicates that transitional epithelial cells are prone to senescence and, hence, are a new player involved in senescence-associated lung fibrosis. Understanding the complex interplay of cell types and cellular regulatory factors contributing to alveolar epithelial progenitor senescence will be crucial to developing targeted therapies to mitigate their downstream profibrotic sequelae and to promote normal alveolar repair.NEW & NOTEWORTHY With an aging population, lung fibrotic diseases are becoming a global health burden. Dysfunctional repair of the alveolar epithelium is a key causative process that initiates lung fibrosis. Normal alveolar regeneration relies on functional progenitor cells; however, the senescence of these cells, which increases with age, hinders their ability to contribute to repair. Here, we discuss studies on the control and consequence of progenitor cell senescence in fibrosis and opportunities for research.

Keywords: SASP; epithelial cells; fibrosis; progenitor cells; senescence.

Graphical abstract

Figure 1.

Alveolar progenitor cells. Various epithelial cells in the distal airways of lungs can generate alveolar type 2 (AT2) cells. These bipotent progenitor cells include club cells, ciliated cells, tuft cells, pulmonary neuroendocrine cells (PNECs), basal cells, and respiratory airway secretory cell (RAS)/alveolar type 0 (AT0) cells. Except for basal cells, which are found in human and not mouse airways, these distal airway progenitor epithelial cells are found in human and mouse lungs, and some can self-renew. AT2 cells in the alveolar compartment can self-renew and differentiate into AT1 cells via a transitional cell type. (Created with BioRender.com with permission).

Figure 2.

Transcriptomic senescence score of alveolar epithelial progenitor cells in idiopathic pulmonary fibrosis (IPF). A: uniform manifold approximation and projection (UMAP) visualization of alveolar progenitor epithelial cells (AT2 and transitional cells). B: average expression of alveolar type 2 (AT2) and transitional cell common markers and transcriptomic senescence score of each cell type in control and IPF. Data are described in two metrics: gene expression and the percentage of expressing cells.