Alveolar epithelial regeneration in the aging lung

Abstract

Advancing age is the most important risk factor for the development of and mortality from acute and chronic lung diseases, including pneumonia, chronic obstructive pulmonary disease, and pulmonary fibrosis. This risk was manifest during the COVID-19 pandemic, when elderly people were disproportionately affected and died from SARS-CoV-2 pneumonia. However, the recent pandemic also provided lessons on lung resilience. An overwhelming majority of patients with SARS-CoV-2 pneumonia, even those with severe disease, recovered with near-complete restoration of lung architecture and function. These observations are inconsistent with historic views of the lung as a terminally differentiated organ incapable of regeneration. Here, we review emerging hypotheses that explain how the lung repairs itself after injury and why these mechanisms of lung repair fail in some individuals, particularly the elderly.

Figure 1. Repair of the alveolar epithelium after lung injury.

(A) Alveolar epithelial type II (AT2) cells are small cuboidal cells that serve as a partially committed progenitor population. AT2 cells are required for the differentiation and maintenance of tissue-resident alveolar macrophages and are maintained by signals from adjacent mesenchymal cells, including Wnt2⁺ fibroblasts. Alveolar epithelial type I (AT1) cells are large flat cells that can spread over more than one alveolus. Their differentiation and maintenance in the niche also require signals from the adjacent mesenchyme, including Wnt5a⁺ fibroblasts. (B) In response to injury, AT2 cells undergo asymmetric division, with the smaller daughter cell regenerating the AT2 cell and the larger daughter cell differentiating into an AT1 cell. Single-cell RNA sequencing of the lung in murine models of injury, repair, and fibrosis and patients with pulmonary fibrosis identified a population of transitional cells with intermediate phenotypes between AT1 and AT2 cells that accumulate in areas of fibrosis. Transitional cells and profibrotic monocyte-derived alveolar macrophages recruited in response to epithelial injury drive the differentiation of fibroblasts into an intermediate phenotype characterized by expression of Sfrp1 and subsequently a myofibroblast, characterized by Cthrc1. Tregs provide signals that directly or indirectly enhance epithelial repair.

Figure 2. The integrated stress response and cell differentiation.

(A) Integrated stress response (ISR) signaling. ISR activation inhibits global protein synthesis but induces ATF4 translation, both of which are improved by the ISR inhibitor (ISRIB). (B) Cell-autonomous and environmental signals during aging may contribute to activation of the ISR that serves as a barrier to AT2 differentiation. This could result in the accumulation of transitional cells that may preclude normal repair.