EXPLORING MUCOCILIARY EPITHELIAL PLASTICITY IN XENOPUS: ENVIRONMENTAL, FUNCTIONAL, AND TRANSLATIONAL INSIGHTS

Kourtnie Whitfield

The mucociliary epithelium is a specialized epithelial type that combines a semi-permeable mucus barrier with ciliary beating to generate mucociliary clearance. This epithelial type is found across diverse contexts, including the embryonic epidermis of frogs and the lining of the mammalian respiratory tract. The ability for mucociliary epithelial tissue to be responsive to internal and external cues is critical for adequate protection from the environment. However, modulators of mucociliary epithelial development that mediate plasticity are not well characterized. Exogenous and endogenous signals that regulate developmental processes, such as cell differentiation, proliferation, morphology, and secretion, often coordinate through conserved signaling pathways that also influence ion flux across the epithelium. This dissertation tests hypotheses on intrinsic and environmental signals that regulate mucociliary epithelial plasticity, using the frog embryo, Xenopus, as a model linking our findings throughout. The first chapter finds that the amphibian embryo epidermis is plastic in response to elevated water salinity, and that the extent of plasticity in a frog species is associated with reduced growth and developmental deficits from salt stress. This chapter also demonstrates the relationship between the mucus barrier and ionic homeostasis and the role of mucociliary epithelia as a critical embryo defense mechanism. The second- and third-chapters test whether intrinsic signaling of the cytokine hormone, leptin, regulates mucus secretion and cell composition in the X. tropicalis embryo epidermis. Our findings suggest that leptin signaling occurs in autocrine and exocrine manners, regulated via a mucus-secreting cell type (small secretory cells (SSCs)) and that leptin promotes mucus secretion, but not mucus production. Additionally, leptin-induced mucus secretion requires extracellular calcium, likely through apical ion transporters activated by kinase signaling pathways, again highlighting the mucus barrier-ionic homeostasis connection. Leptin signaling also regulated epidermal cell density when signaling was altered throughout the embryonic period and additionally affected SSC abundance within specific developmental windows. Previous work in our lab has demonstrated that leptin signaling promotes larval development and regeneration in Xenopus laevis, and these two chapters further support leptin’s role in epithelial development. In the fourth chapter, we apply our findings of leptin signaling effects to human airway epithelia from pediatric donors, to test the hypothesis that leptin signaling alters epithelial surface structure and innate immune responses to viral infection. We found interesting differences in the epithelial landscape between the frog embryo epidermis vs. the airway epithelium that led to differences in structural measurements obtained between the two. Even so, we found that leptin signaling targeted ciliary processes and regulated the area of the cilia “carpet” covering the epithelium, that suggests either loss of cilia on multiciliated cells or potential goblet cell hyperplasia or hypertrophy. However, we did not find direct effects of leptin on mucin expression or innate immune factor production. Additionally, we observed donor-specific responses, and further research is needed to understand inter-individual variability to leptin sensitivity. These results provide insights into leptin’s specific role in airway epithelial dysfunction that’s present in pediatric asthma and complicated by childhood obesity, where targeted and individualized therapies are needed. Combined, mechanisms of mucociliary epithelial plasticity examined in this dissertation may contribute to a wide array of research in addition to vertebrate embryo plasticity and respiratory research, but also studies in wound healing and regeneration, gastrointestinal epithelia, or kidney epithelia.

EXPLORING MUCOCILIARY EPITHELIAL PLASTICITY IN XENOPUS: ENVIRONMENTAL, FUNCTIONAL, AND TRANSLATIONAL INSIGHTS

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