Niche Cells and Signals that Regulate Lung Alveolar Stem Cells In Vivo

Abstract

The distal lung is a honeycomb-like collection of delicate gas exchange sacs called alveoli lined by two interspersed epithelial cell types: the cuboidal, surfactant-producing alveolar type II (AT2) and the flat, gas-exchanging alveolar type I (AT1) cell. During aging, a subset of AT2 cells expressing the canonical Wnt target gene, Axin2, function as stem cells, renewing themselves while generating new AT1 and AT2 cells. Wnt activity endows AT2 cells with proliferative competency, enabling them to respond to activating cues, and simultaneously blocks AT2 to AT1 cell transdifferentiation. Acute alveolar injury rapidly expands the AT2 stem cell pool by transiently inducing Wnt signaling activity in "bulk" AT2 cells, facilitating rapid epithelial repair. AT2 cell "stemness" is thus tightly regulated by access to Wnts, supplied by a specialized single-cell fibroblast niche during maintenance and by AT2 cells themselves during injury repair. Two non-AT2 "reserve" cell populations residing in the distal airways also contribute to alveolar repair, but only after widespread epithelial injury, when they rapidly proliferate, migrate, and differentiate into airway and alveolar lineages. Here, we review alveolar renewal and repair with a focus on the niches, rather than the stem cells, highlighting what is known about the cellular and molecular mechanisms by which they control stem cell activity in vivo.

Thoughts on the alveolar phase of COVID-19

“…In most forms of lung injury there is type II cell proliferation, development of transitional type II cells, and differentiation into type I cells, which leads to restoration of the alveolar epithelium ( Fig. 3 C ) ( 17 , 28 , 32 ). This might not occur in severely damaged areas of the lung in COVID-19.…”

“…3 D ) ( 19 , 36 , 43 , 47 ). Lineage tracing has shown that these cells are heterogeneous ( 17 , 36 , 45 , 47 ). There are nonlineage labeled airway cells that express keratin 5 and migrate into the alveolar compartment ( 27 , 36 , 43 ).…”

Progenitor identification and SARS-CoV-2 infection in human distal lung organoids

“…In humans, basal stem cells span the entire airway tree in contrast to mouse where club cells 2 and/or Secretoglobin 1A1 (SCGB1A1)-expressing non-club cells 3 renew the distal bronchioles during aging. In the gas exchange region, murine alveolar epithelial type II (AT2) cells generate AT1 and AT2 cells during homeostasis 4,5 , and additional progenitors are recruited by severe injury 3,[6][7][8][9] . The presence and/or roles of facultative progenitors in human lung is unknown.…”

Immunoglobulin-producing AT2-like cells secrete IgA into the extracellular matrix in pulmonary fibrosis

“…Lung alveolar progenitor cells can self-renew, proliferate and replenish damaged alveolar epithelium (Juul et al, 2020). When they proliferate abnormally, they cause alveolar structural disorders (Parimon et al, 2020;Yao et al, 2021).…”