Injury Induces Direct Lineage Segregation of Functionally Distinct Airway Basal Stem/Progenitor Cell Subpopulations

Abstract

Summary Following injury, stem cells restore normal tissue architecture by producing the proper number and proportions of differentiated cells. Current models of airway epithelial regeneration propose that distinct cytokeratin 8-expressing progenitor cells, arising from p63+ basal stem cells, subsequently differentiate into secretory and ciliated cell lineages. We now show that immediately following injury, discrete subpopulations of p63+ airway basal stem/progenitor cells themselves express Notch pathway components associated with either secretory or ciliated cell fate commitment. One basal cell population displays intracellular Notch2 activation and directly generates secretory cells; the other expresses c-myb and directly yields ciliated cells. Furthermore, disrupting Notch ligand activity within the basal cell population at large disrupts the normal pattern of lineage segregation. These non-cell autonomous effects demonstrate that effective airway epithelial regeneration requires intercellular communication within the broader basal stem/progenitor cell population. These findings have broad implications for understanding epithelial regeneration and stem cell heterogeneity.

Lung organoids: current uses and future promise

“…Recently, genetic techniques have been used to kill very selectively most basal cells. In response, some Club secretory cells undergo reprogramming to become Krt5 + Trp63 + basal cells that can function as stem cells in vivo (Pardo-Saganta et al, 2015;Tata et al, 2013). Taken together, these injury/repair studies have revealed remarkable and rather unexpected flexibility in the way in which basal cells, luminal precursors and differentiated secretory cells can work together to maintain and repair the pseudostratified mucociliary epithelium of the mouse airway.…”

Take a deep breath and digest the material: organoids and biomaterials of the respiratory and digestive systems

“…[112][113][114][115][116][117] Common airway disorders include chronic obstructive pulmonary disease and asthma, for which airway organoids could provide useful models. [4] Most recent studies have shown organoids that represent early stages of lung development can be injected with respiratory syncytial virus and the lung epithelium sloughs off, which is a known consequence of this virus.…”

GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells

“…Specifically, recent studies have implicated Notch3 in promoting the differentiation of adult basal stem cells into parabasal progenitors and Notch1 and 2 in fate selection between secretory and ciliated linages (Rock et al, 2011b;Danahay et al, 2015;Mori et al, 2015;Pardo-Saganta et al, 2015). ChIP-Seq has shown Grhl2 occupancy of binding sites near NOT CH1, NOT CH3, JAG1, and JAG2 (Gao et al, 2013).…”

“…Krt5 + Trp63 + BCs of the pseudostratified mucociliary epithelium both self-renew and give rise to both Foxj1 + ciliated and secretory cells. This differentiation involves notch signaling and is thought to proceed via Trp63 + progenitors committed to either lineage pathway (yellow or blue nuclei; Mori et al, 2015;Pardo-Saganta et al, 2015;Watson et al, 2015). As progenitors and their descendants integrate into the epithelium, they acquire apical-basal polarity and apical-junctional complexes mediating barrier function.…”

“…At steady state, these basal cells (BCs) are relatively quiescent, but after a loss of luminal cells they proliferate and differentiate into ciliated and secretory cells (Borthwick et al, 2001;Hogan et al, 2014). Considerable progress is being made in understanding the transcriptional circuits and signaling pathways that regulate the self-renewal of BCs and the lineage choices of their descendants (Rock et al, 2011b;Tata et al, 2013;Paul et al, 2014;Tadokoro et al, 2014;Zhao et al, 2014;Danahay et al, 2015;Mori et al, 2015;Pardo-Saganta et al, 2015;Watson et al, 2015). However, less is known about the cellular mechanisms that drive morphological changes in the daughters of the BCs as they acquire apical-basal polarity and integrate seamlessly into the epithelium.…”