The epithelial-to-mesenchymal transition (EMT) and the unjamming transition (UJT) each comprises a gateway to cellular migration, plasticity and remodeling, but the extent to which these core programs are distinct, overlapping, or identical has remained undefined. Here, we triggered partial EMT (pEMT) or UJT in differentiated primary human bronchial epithelial cells. After triggering UJT, cell-cell junctions, apico-basal polarity, and barrier function remain intact, cells elongate and align into cooperative migratory packs, and mesenchymal markers of EMT remain unapparent. After triggering pEMT these and other metrics of UJT versus pEMT diverge. A computational model attributes effects of pEMT mainly to diminished junctional tension but attributes those of UJT mainly to augmented cellular propulsion. Through the actions of UJT and pEMT working independently, sequentially, or interactively, those tissues that are subject to development, injury, or disease become endowed with rich mechanisms for cellular migration, plasticity, self-repair, and regeneration.

The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

9Every organ surface and body cavity is lined by a confluent collective of epithelial cells. In 10 homeostatic circumstances the epithelial collective remains effectively solid-like and 11 sedentary. But during morphogenesis, remodeling or repair, as well as during malignant 12 invasion or metastasis, the epithelial collective becomes fluid-like and migratory 1-4 . This 13 conversion from sedentary to migratory behavior has traditionally been understood as a 14 manifestation of the epithelial-to-mesenchymal transition (EMT) or the partial EMT (pEMT) 5-8 . 15 However, in certain contexts this conversion has been attributed to the recently discovered 16unjamming transition (UJT), in which epithelial cells move collectively and cooperatively 9-11 . 17UJT and pEMT share certain aspects of collective cellular migration, but the extent to which 18 these processes are distinct, overlapping or perhaps even identical has remained undefined. 19 Using the confluent layer of well-differentiated primary human bronchial epithelial (HBE) cells, 20here we triggered UJT by exposing the sedentary layer to mechanical compression 9-12 . Cells 21 thereafter migrated cooperatively, aligned into packs locally, and elongated systematically. 22Nevertheless, cell-cell junctions, apico-basal polarity, and barrier function remained intact in 23 response, and mesenchymal markers remained unapparent. As such, pEMT was not evident. 24When we triggered pEMT and associated cellular migration by exposing the sedentary layer to 25 TGF-β1, metrics of UJT versus pEMT diverged. To account for these striking physical 26 observations a new mathematical model attributes the effects of pEMT mainly to diminished 27 junctional tension but attributes those of UJT mainly to augmented cellular propulsion. 28Together, these findings establish that UJT is sufficient to account for vigorous epithelial 29 layer migration even in the absence of pEMT. Distinct gateways to cellular migration therefore 30 become apparent -UJT as it might apply to migration of epithelial sheets, and EMT/pEMT as it 31 might apply to migration of mesenchymal cells on a solitary or collective basis, activated 32 during development, remodeling, repair or tumor invasion. Through the actions of UJT and 33 pEMT working independently, sequentially, or interactively, living tissue is therefore seen to 34 comprise an active engineering material whose modules for plasticity, self-repair and 35 regeneration, are far richer than had been previously appreciated. 36 2 Since its discovery in 1982, the epithelial-to-mesenchymal transition (EMT) has been intensively 37 studied and well-characterized 6, 13, 14 . EMT is marked by progressive loss of epithelial character, 38including disrupted apico-basal polarity, disassembled cell-cell junctions, and impaired epithelial layer 39 integrity and barrier function. This loss of epithelial character is accompanied by progressive gain of 40 mesenchymal character, including gain of front-back polarity, activation of EMT-inducing transcription 41 factors, and e...

Chronic disease results from the failure of tissues to maintain homeostasis. In the lung, coordinated repair of the epithelium is essential for preserving homeostasis. In animal models and human lung disease, airway epithelial cells mobilize in response to lung injury, resulting in the formation of airway-like cysts with persistent loss of functional cell types and parenchymal architecture. Using live-cell imaging of human lung epithelial cultures and mouse precision-cut lung slices, we demonstrated that distal airway epithelia are aberrantly fluidized both after injury and in fibrotic lung disease. Through transcriptomic profiling and pharmacologic stimulation of epithelial cultures, we identified interleukin-6 (IL-6) signaling as a driver of tissue fluidization. This signaling cascade occurred independently of canonical Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling but instead was dependent on a downstream SRC family kinase (SFK)–yes-associated protein (YAP) axis. Airway epithelial-fibroblast cocultures revealed that the fibrotic mesenchyme acts as a source of IL-6 family cytokines, which drive airway fluidization. Inhibition of the IL-6–SFK–YAP cascade was sufficient to prevent fluidization in both in vitro and ex vivo models. Last, we demonstrated a reduction in fibrotic lung remodeling in mice through genetic or pharmacologic targeting of IL-6–related signaling. Together, our findings illustrate the critical role of airway epithelial fluidization in coordinating the balance between homeostatic lung repair and fibrotic airspace remodeling.