Epithelial plasticity in COPD results in cellular unjamming due to an increase in polymerized actin

Abstract

The airway epithelium is subjected to insults such as cigarette smoke (CS), a primary cause of Chronic Obstructive Pulmonary Disease (COPD) and serves as an excellent model to study cell plasticity. Both CS-exposed and COPD-patient derived epithelia (CHBE) display quantitative evidence of cellular plasticity, with loss of specialized apical features and a transcriptional profile suggestive of partial epithelial to mesenchymal transition, albeit with distinct cell motion indicative of cellular unjamming. These injured/diseased cells have an increased fraction of polymerized actin, due to loss of the actin-severing protein, cofilin-1. Decreasing polymerized actin restores the jammed state in both CHBE and CS exposed epithelia, indicating that the fraction of polymerized actin is critical in unjamming the epithelia. Kinetic energy spectral analysis suggests that loss of cofilin-1 results in unjamming, similar to that seen with both CS exposure and in CHBE cells. Our data suggest that in response to chronic injury, although epithelial cells display evidence of pEMT, their movement is more consistent with cellular unjamming. Inhibitors of actin polymerization rectify the unjamming features of the monolayer.

Human Leukocyte Antigen Genotyping of Idiopathic Subglottic Stenosis

“…This inflammation, when sustained inappropriately, can culminate in fibrotic tissue remodeling and physiologic impairment. [41][42][43][44] Recent published reports implicating defective airway epithelium in iSGS 8,46,47 may help explain the lack of HLA association demonstrated in this study. Interestingly, iSGS epithelium demonstrates both decreased progenitor subsets and reduced epithelial thickness when compared to healthy controls.…”

Cofilin-1 and profilin-1 expression in lung microvascular endothelial cells exposed to titanium dioxide nanoparticles

“…These results can be partly explained by recent experiments. [40][41][42] Injured epithelial cells exposed to cigarette smoke in COPD have an increased fraction of polymerized actin, due to loss of the actin-severing protein cofilin-1. 40 Further studies are needed to clarify the underlying signaling pathways and implications of these findings for airway diseases.…”

“…These injured/diseased cells have an increased fraction of polymerized actin, due to the loss of the actin-severing protein, cofilin-1. 29 Counteracting cofilin-1 is profilin-1, an actin-binding protein that promotes actin polymerization in vitro, 25,26 endothelial cell migration and proliferation. 27 A requirement for dynamic actin association and dissociation is rendered by reversible Ser 71 phosphorylation and dephosphorylation.…”

Dysfunctional Epithelial Barrier Is Characterized by Reduced E‐Cadherin in Idiopathic Subglottic Stenosis

“…Epithelial cells were differentiated in vitro in PneumaCult™-ALI (STEMCELL Technologies Inc, Seattle, WA) medium for 4 weeks. [13][14][15] Functional studies of cultured epithelial cells were quantified using transepithelial-electrical resistance (TEER), FITC-Dextran permeability assay, and cilia beating frequency (CBF). Finally, epithelial tight junction protein expression of cultured cells was assessed using immunoblot assay and immunofluorescence.…”

“…After reaching 95% confluency, cells were differentiated in PneumaCult™-ALI (STEMCELL Technologies) for 4 weeks into pseudostratified epithelium. [13][14][15]…”