van Es, J. H. | bioRxiv Science

bioRxiv2025

A human organoid model of alveolar regeneration reveals distinct epithelial responses to interferon-gamma

Chronic obstructive pulmonary disease is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the alveolar epithelium. Here, we describe a feeder- and serum-free primary adult human organoid model to investigate how inflammation influences alveolar regeneration. We achieve long-term expansion of multipotent progenitor-like cells, while an alveolar type 2 (AT2) maturation protocol enhances surfactant production and supports tubular myelin formation. Introducing a LATS inhibitor to the expansion condition induces alveolar type 1 (AT1) differentiation while maintaining AT2 cells. Using this platform, we find that interferon-gamma exerts cytotoxic effects on AT1 cells while promoting the growth of regenerating AT2 cells, illustrating how a single inflammatory stimulus can have divergent effects on alveolar epithelial cell types. These findings underscore the nuanced influence of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a reductionist platform for mechanistic studies, aimed to identify strategies to enhance alveolar regeneration.

cell biology↗

bioRxiv2024

Lgr5+ ductal cells of von Ebner's glands are stem cells for turnover of posterior tongue taste buds

Taste bud cells have a limited lifespan and must be continuously replaced along with the papilla epithelium in which they reside. Previous work has shown that expression of leucine- rich G protein-coupled receptor 5 (Lgr5), a Wnt pathway agonist, serves as a marker of adult stem/progenitor cells for taste buds located in posterior tongue (circumvallate and foliate), but not anterior tongue (fungiform), taste papillae. However, the specific location/niche of the Lgr5-expressing cells supporting renewal and their phenotypic properties have not been fully explored. To address this, the genesis and fate of Lgr5+ cells were examined in developing and adult mice using genetic reporter strains. Evidence from Lgr5-lacZ and Lgr5- GFP mice shows that, while Lgr5 is broadly expressed in the epithelium of nascent circumvallate papillae and their trenches during embryonic development, it becomes concentrated within the ducts of adjacent von Ebners salivary glands during the first postnatal week, co-incident with the appearance of differentiated taste buds. In posterior tongue taste papillae of adult animals, sites of highest Lgr5 expression are found in excretory ducts, restricted to the outer (basal) layer of the bi-layered excretory zone. These Lgr5+ cells are immunoreactive for keratin 14, like cells in the basal layer of extragemmal taste epithelium, and for Sox9, a marker of exocrine gland duct cells. Lineage tracing experiments with an Lgr5-EGFP-IRES-CreERT2;R26-mTmG reporter show that Lgr5+ ductal cells become labeled one day following Cre induction, prior to the appearance of descendent cells in taste buds and extragemmal epithelium. These data support a role for Lgr5+ ductal cells as stem cells and suggest that a cooperative interaction exists between posterior taste epithelium and its associated salivary glands in taste cell turnover.

developmental biology↗