A cell‐centric view of lung alveologenesis

Abstract

Lung alveologenesis, formation of the alveolar region, allows sufficient gas exchange surface to be packed inside the chest cavity yet with orderly connection to the trachea. The real-life alveolar region, however, bears little resemblance to idealized cartoons owing to its three-dimensional nature, nonuniform shape, and mostly air-filled void. This morphological complexity is matched by its cellular complexity-comprised of intermixed and often tangled cells of the epithelial, mesenchymal, endothelial, and immune lineages. Modern imaging, genetics, and genomics are shedding light on and updating traditional views of alveologenesis. Accordingly, this review describes a cellcentric 3-phase definition of alveologenesis and discusses its failure in diseases and possible reactivation during regeneration.

Differential chromatin binding of the lung lineage transcription factor NKX2-1 resolves opposing murine alveolar cell fates in vivo

“…4b, c). Although SOX9 progenitors continuously exit branch tips and become AT1 and AT2 cell precursors at E16.5 25,26 , such early molecular differentiation was placed by Monocle within the progenitor branch and prior to the AT1/AT2 divergence (Fig. 4b, c).…”

Three-axis classification of mouse lung mesenchymal cells reveals two populations of myofibroblasts

“…These perinuclear-PDGFRA contractile cells occupied grooves over the folding alveolar surface during classical alveologenesis (P3-P14) (Vila Ellis and Chen, 2020) and thus corresponded to alveolar myofibroblasts (Fig. 3C).…”

“…The proximal CDH4 zone corresponded to the alveolar ducts – tubular extensions of the airways but bordered by alveolar type 1 and type 2 cells. Arising from branch stalks as the airways did, alveolar ducts had wider airspace than the surrounding alveoli and could be best identified as they extended toward the lateral edge, instead of the lobe surface where tissue geometry made tubes less recognizable as they were shorter and interrupted by branching (Vila Ellis and Chen, 2020; Yang and Chen, 2014). We also found an HHIP antibody that marked cellular projections that largely aligned with CDH4, but also perinuclear regions for cell enumeration (Fig.…”

Intermediary role of lung alveolar type 1 cells in epithelial repair upon Sendai virus infection

“…As the first barrier against microbial and chemical agents, the otherwise quiescent lung epithelium has evolved robust repair mechanisms that, in the alveolar region, activate a facultative stem cell population – alveolar type 2 (AT2) cells, which have attracted most attention in the field (Barkauskas et al, 2013; Desai et al, 2014; Hogan et al, 2014). In contrast, alveolar type 1 (AT1) cells, constituting 95% of the alveolar surface, are often considered a passive structural component to be injured and then replaced by AT2 cells, but are likely a key component of the lung’s holistic reaction to injury due to their sheer mass (Chen, 2017; Vila Ellis and Chen, 2020). Our limited knowledge of AT1 cell biology in injury-repair stems partly from their expansive and ultrathin morphology that spatially uncouples the nucleus from cellular extensions such that cytokeratin, junctional, or nuclear staining alone is inadequate to study AT1 cells (Yang et al, 2016).…”

“…Conceptually, the alveolar epithelium can be unfurled into a 2D surface – an imagery evoked when analogizing the human lung to a half tennis court – that is predominantly AT1 cell surface and sprinkled with AT2 cells (Weibel, 2009). Accordingly, injury-repair could be (1) in situ healing similar to wound healing as a result of cell expansion, proliferation, and migration – a process also artificially invoked during re-epithelialization of decellularized lungs (Uriarte et al, 2018), or (2) de novo growth around the border of the tennis court – a likely process during post-pneumonectomy compensatory growth where there is no direct injury to the existing surface (Lee and Rawlins, 2018; Vila Ellis and Chen, 2020). Regardless, it is integral to our understanding of lung injury-repair to delineate how the majority of the epithelial surface, or essentially the AT1 cell, responds and contributes.…”