Please use this identifier to cite or link to this item: http://arks.princeton.edu/ark:/88435/dsp01hh63t003x
 Title: EVOLUTION-GUIDED INVESTIGATION OF DEVELOPMENTAL MECHANISMS IN LUNGS OF TERRESTRIAL VERTEBRATES Authors: Palmer, Michael Axel Advisors: Nelson, Celeste M Contributors: Chemical and Biological Engineering Department Keywords: evolutionlungsmechanicsmorphogenesissmooth muscletissue engineering Subjects: Developmental biologyEvolution & developmentBioengineering Issue Date: 2021 Publisher: Princeton, NJ : Princeton University Abstract: The function of the lung is closely coupled to its structural anatomy, which varies greatly across vertebrates. As it develops, the avian lung transforms from an initially terminally branched epithelial tree to a continuous circuit of airways via a large-scale epithelial fusion event. We investigated airway fusion in the domestic chicken, Gallus gallus, and found that it is not stereotyped, instead occurring between airways that are stochastically located adjacent to each other. Prior to fusion, the fusing airways bend away from each other, then initiate new branches which contain the cells that form the first contact. These changes in epithelial shape coincide with the differentiation of smooth muscle cells that wrap the airways, suggesting a physical role for smooth muscle in shaping the pre-fusion epithelium. From the resulting nascent branches, individual epithelial cells extend cytoskeletal protrusions that form a bridge with their target airway. Additional cells then join the fusion site and build a bilayered epithelium between the two airways which is later cleared by apoptosis. In contrast to the complexity of the avian lung, the lizard lung consists of only a single hollow chamber with rudimentary corrugations along its surface. We examined early development of reptile lungs using the brown anole, Anolis sagrei, as a model organism and found that smooth muscle is present in a hexagonal mesh-like arrangement surrounding the epithelium. Using next-generation sequencing we discovered that smooth muscle differentiation is controlled by similar pathways as in the developing mouse lung, and that disrupting differentiation of smooth muscle prevents the formation of the shallow epithelial corrugations. Using timelapse imaging coupled with experiments designed to manipulate fluid pressure and muscle contractility, we revealed that the hexagonal smooth muscle geometry self-assembles in response to stresses downstream of mechanical forces, and that this is required for epithelial morphogenesis. We created a bio/synthetic model using these principles to deform a thin polymer film into a corrugated structure reminiscent of what is observed in vivo. Overall, these observations suggest a conserved evolutionary role for smooth muscle in mechanically shaping lung epithelia, albeit in patterns and final architectures that vary across classes of vertebrates, and present novel ideas for tissue engineering. URI: http://arks.princeton.edu/ark:/88435/dsp01hh63t003x Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog: catalog.princeton.edu Type of Material: Academic dissertations (Ph.D.) Language: en Appears in Collections: Chemical and Biological Engineering

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