Evaluating the role of epithelial basal cells in laryngeal homeostasis and disease development

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ABSTRACT The larynx requires protection from the ~25 million inhaled insults encountered daily during fulfillment of its normal functions including breathing, coughing, swallowing, and in humans, voice production. An epithelium forms a critical first protective barrier on the surface of the larynx. Under normal conditions, the epithelium relies on homeostatic regenerative mechanisms. The basal cell (BC) layer of the epithelium is believed to represent a reservoir of progenitor cells for the formation and regeneration of differentiated epithelium. However, pathological changes, or remodeling, occurs in the composition and organization of the laryngeal epithelium in response to inhaled insults, notably cigarette smoke (CS). Remodeling affects the ability of the epithelium to function as an effective barrier and predisposes the tissue to disease development. Despite the prevalence and likely importance of epithelial remodeling in CS-induced laryngeal disease, its etiology is poorly understood. This is due to a lack of basic knowledge of the mechanisms which dictate laryngeal epithelial homeostatic regeneration and permanent tissue remodeling linked to CS. Specifically, little is known about the biology of the BC population in normal epithelial homeostasis, injured, or diseased conditions. A paucity of research on laryngeal BC biology serves as a major barrier in the development of therapies to prevent and treat CS-diseased vocal folds. To address this unmet need, we propose to test the central hypothesis that BC are critical to the formation and maintenance of normal laryngeal epithelium and CS-induced alterations in BC biology are associated with epithelial remodeling and human disease development. We will test this hypothesis using a normal mouse model (AIM 1) and in vivo and in vitro models of CS exposure (AIM 2) to study laryngeal BC properties in differentiated epithelium, primary culture, and physiologically relevant three-dimensional epithelial cell culture systems. We also propose to evaluate how our in vivo and in vitro findings in mice relate to the human condition by evaluating the biology of BC in human laryngeal specimens from patients with Reinke’s edema, a common CS-induced laryngeal disease (AIM 3). Completion of these aims will demonstrate that BC have a central and irreplaceable role in laryngeal epithelial biology- they function as progenitor cells for normal epithelium and alterations in BC biology are implicated in disease development. Findings will have significant theoretical and clinical impact and will provide novel new insights into the mechanism underlying laryngeal and vocal fold epithelial regeneration. Targeting specific biologic pathways that mediate CS-induced derangements in BC biology may represent innovative therapeutic targets to prevent development and progression of CS- and other smoke-mediated voice disorders.