The vertebrate lung develops via a process known as branching morphogenesis, wherein subgroups of epithelial cells are instructed reiteratively to form clefts or buds and thereby generate a space-filling tree with a sufficient surface area for gas exchange to support breathing after birth. An aberrant mechanical environment within the thoracic cavity can disrupt branching and cause fetal pulmonary hypoplasia, a major cause of respiratory insufficiency of the newborn. It is unclear how mechanical stresses control or disrupt the branching program. Here, we describe experiments combining tissue engineering approaches with investigations of intact embryonic lungs to define how mechanical stresses are transduced into gene expression changes that drive branching morphogenesis. Engineered lung tissues and computational models will be used to predict the role of mechanical stresses in branch site initiation.
In Specific Aim 1, we will determine whether and how mechanical stresses regulate branching morphogenesis of engineered embryonic mouse lung tissues and intact chick and mouse embryonic lungs.
In Specific Aim 2, we will define the mechanically induced gene expression changes that drive lung branching. To our knowledge, this work will represent the first comprehensive analysis of mechanically responsive genes in branching morphogenesis in culture or in vivo. We expect that the gene expression patterns revealed will uncover new avenues to explore for medical treatment of mechanically-induced diseases such as fetal pulmonary hypoplasia.

Public Health Relevance

Organ development requires exquisite control processes to ensure proper patterning and generation of functional forms. Increasing evidence suggests that mechanical stresses are involved in the development of the branching patterns of the lung and other tree-like organs, and that aberrant mechanical stresses can cause human fetal pulmonary diseases. We present here an integrated approach to define precisely how mechanical stresses are converted into gene expression changes that drive branching morphogenesis of embryonic lung tissues, which will enable future studies to treat human fetal pulmonary disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-CB-P (55))
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Lin, Sara
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Princeton University
Schools of Arts and Sciences
United States
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Nerger, Bryan A; Siedlik, Michael J; Nelson, Celeste M (2017) Microfabricated tissues for investigating traction forces involved in cell migration and tissue morphogenesis. Cell Mol Life Sci 74:1819-1834
Siedlik, Michael J; Manivannan, Sriram; Kevrekidis, Ioannis G et al. (2017) Cell Division Induces and Switches Coherent Angular Motion within Bounded Cellular Collectives. Biophys J 112:2419-2427
Goodwin, Katharine; Nelson, Celeste M (2017) Generating tissue topology through remodeling of cell-cell adhesions. Exp Cell Res 358:45-51
Pang, Mei-Fong; Siedlik, Michael J; Han, Siyang et al. (2016) Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells. Cancer Res 76:5277-87
Piotrowski-Daspit, Alexandra S; Tien, Joe; Nelson, Celeste M (2016) Interstitial fluid pressure regulates collective invasion in engineered human breast tumors via Snail, vimentin, and E-cadherin. Integr Biol (Camb) 8:319-31
Siedlik, Michael J; Varner, Victor D; Nelson, Celeste M (2016) Pushing, pulling, and squeezing our way to understanding mechanotransduction. Methods 94:4-12
Navis, Adam; Nelson, Celeste M (2016) Pulling together: Tissue-generated forces that drive lumen morphogenesis. Semin Cell Dev Biol 55:139-47
Nelson, Celeste M (2016) On Buckling Morphogenesis. J Biomech Eng 138:021005
Tzou, Daniel; W Spurlin 3rd, James; Pavlovich, Amira L et al. (2016) Morphogenesis and morphometric scaling of lung airway development follows phylogeny in chicken, quail, and duck embryos. Evodevo 7:12
Paluch, Ewa K; Nelson, Celeste M; Biais, Nicolas et al. (2015) Mechanotransduction: use the force(s). BMC Biol 13:47

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