A single cell Wnt signaling niche maintains stemness of alveolar type 2 cells
By Ahmad N. Nabhan, D. Brownfield, Pehr Harbury, M. Krasnow, T. Desai. Science, 2018
639 citations recorded by the source corpus.
Fibroblasts as lung stem cell niche Each breath that we take provides oxygen to the bloodstream via tiny sacs in the lung called alveoli. AT1 cells line the alveoli and mediate gas exchange, whereas AT2 cells secrete lung surfactant. A subset of AT2s also serve as stem cells that slowly generate new alveolar cells throughout adult life. Nabhan et al. show that the rare AT2 stem cells have a special niche next to a fibroblast secreting Wnts. This Wnt activity is needed to select and maintain the stem cells. Injury expands the stem cell pool by transiently inducing autocrine Wnts in other surfactant-secreting alveolar cells. This simple but expandable niche sustains oxygen delivery, and it is co-opted in lung cancer. Science, this issue p. 1118 Juxtacrine Wnts select and maintain lung stem cells, and injury-induced autocrine Wnts recruit stem cells. Alveoli, the lung’s respiratory units, are tiny sacs where oxygen enters the bloodstream. They are lined by flat alveolar type 1 (AT1) cells, which mediate gas exchange, and AT2 cells, which secrete surfactant. Rare AT2s also function as alveolar stem cells. We show that AT2 lung stem cells display active Wnt signaling, and many of them are near single, Wnt-expressing fibroblasts. Blocking Wnt secretion depletes these stem cells. Daughter cells leaving the Wnt niche transdifferentiate into AT1s: Maintaining Wnt signaling prevents transdifferentiation, whereas abrogating Wnt signaling promotes it. Injury induces AT2 autocrine Wnts, recruiting “bulk” AT2s as progenitors. Thus, individual AT2 stem cells reside in single-cell fibroblast niches providing juxtacrine Wnts that maintain them, whereas injury induces autocrine Wnts that transiently expand the progenitor pool. This simple niche maintains the gas exchange surface and is coopted in cancer.
Subfields: Pediatrics, Perinatology and Child Health, Pulmonary and Respiratory Medicine, Surgery
View Paper: https://www.semanticscholar.org/paper/c69fbdcd2c794f43ad4b56608b7073300fc7a94c
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Citations in the corpus
- A molecular cell atlas of the human lung from single cell RNA sequencing (2019, background): “The 58 identified cell populations included 15 epithelial (clusters 1-15), 9 endothelial (16-24), 9 stromal (25-33), and 25 immune (34-58) populations, greater than the number of classical cell types in each compartment (11 epithelial, 5 endothelial, 7 stromal, 20 immune, and 2 neuronal cell types) ”
- Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis (2019, background): “These fi ndings are consistent with the emerging concept that Wnt signaling, particularly in progenitor populations, is optimized through de fi ned epithelial/mesenchymal pairings that comprise a niche (30 – 32).”
- The digestive system is a potential route of 2019-nCov infection: a bioinformatics analysis based on single-cell transcriptomes (2020, background): “In lung alveoli, AT1 epithelial cells are responsible for gas 2 exchange and AT2 cells are in charge of surfactant biosynthesis and 3 self-renewing[31].”
- Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities (2022, background): “Notably, Wnt5a, a common nonclassical Wnt pathway activator, after secretion by fibroblasts, activates the classic Wnt signalling pathway in AT2 cells and inhibits the transdifferentiation of AXIN2 AT2 cells with stem cell activity into AT1 cells, thus maintaining the dryness of AT2 cells.(82,83) Wh”