H1N1 influenza virus infection induces dramatic and permanent alveolar remodeling mediated by p63+ progenitor cell expansion in both mice and some patients with acute respiratory distress syndrome. This persistent lung epithelial dysplasia is accompanied by chronic inflammation, but the driver(s) of this pathology are unknown. This work identified de novo appearance of solitary chemosensory cells (SCCs), as defined by the tuft cell marker doublecortin-like kinase 1, in post-influenza lungs, arising in close proximity with the dysplastic epithelium, whereas uninjured lungs are devoid of SCCs. Interestingly, fate mapping demonstrated that these cells are derived from p63-expressing lineage-negative progenitors, the same cell of origin as the dysplastic epithelium. Direct activation of SCCs with denatonium + succinate increased plasma extravasation specifically in post-influenza virus-injured lungs. Thus we demonstrate the previously unrecognized development and activity of SCCs in the lung following influenza virus infection, implicating SCCs as a central feature of dysplastic remodeling.
SUMMARY
The regulatory effect auxin has on its own transport is
critical in numerous self-organizing plant patterning processes.
However, our understanding of the molecular mechanisms linking auxin
signal transduction and auxin transport is still fragmentary, and
important regulatory genes remain to be identified.To track a key link between auxin signaling and auxin
transport in development, we established an Arabidopsis
thaliana genetic background in which fundamental
patterning processes in both shoot and root were essentially
abolished and the expression of PIN FORMED (PIN) auxin efflux
facilitators was dramatically reduced.In this background, we demonstrate that activating a
steroid-inducible variant of the Auxin Response Factor (ARF)
MONOPTEROS (MP) is sufficient to restore patterning and
PIN gene expression. Further, we show that MP
binds to distinct promoter elements of multiple genetically defined
PIN genes.Our work identifies a direct regulatory link between central,
well-characterized genes involved in auxin signal transduction and
auxin transport. The steroid-inducible MP system directly
demonstrates the importance of this molecular link in multiple
patterning events in embryos, shoots and roots, and provides novel
options for interrogating the properties of self-regulated
auxin-based patterning in planta.
Alveolar type-2 (AT2) cells are necessary for the lung’s regenerative response to epithelial insults such as influenza. However, current methods to expand these cells rely on mesenchymal co-culture, complicating the possibility of transplantation following acute injury. Here we developed several mesenchyme-free culture conditions that promote growth of murine AT2 organoids. Transplanting dissociated AT2 organoids into influenza-infected mice demonstrated that organoids engraft and either proliferate as AT2 cells or unexpectedly adopt a basal cell-like fate associated with maladaptive regeneration. Alternatively, transplanted primary AT2 cells also robustly engraft, maintaining their AT2 lineage while replenishing the alveolar type-1 (AT1) cell population in the epithelium. Importantly, pulse oximetry revealed significant increase in blood-oxygen saturation in primary AT2 recipients, indicating that transplanted cells also confer increased pulmonary function after influenza. We further demonstrated that both acid installation and bleomycin injury models are also amenable to AT2 transplantation. These studies provide additional methods to study AT2 progenitor potential, while serving as proof-of-principle for adoptive transfer of alveolar progenitors in potential therapeutic applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.