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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HL110335-01
Application #
8146718
Study Section
Special Emphasis Panel (ZRG1-CB-P (55))
Program Officer
Lin, Sara
Project Start
2011-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
1
Fiscal Year
2011
Total Cost
$241,500
Indirect Cost
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
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Nerger, Bryan A; Nelson, Celeste M (2018) 3D culture models for studying branching morphogenesis in the mammary gland and mammalian lung. Biomaterials :
Anla?, Ali?ya A; Nelson, Celeste M (2018) Tissue mechanics regulates form, function, and dysfunction. Curr Opin Cell Biol 54:98-105
Kourouklis, Andreas P; Nelson, Celeste M (2018) Modeling branching morphogenesis using materials with programmable mechanical instabilities. Curr Opin Biomed Eng 6:66-73
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
Varner, Victor D; Nelson, Celeste M (2017) Computational models of airway branching morphogenesis. Semin Cell Dev Biol 67:170-176
Goodwin, Katharine; Nelson, Celeste M (2017) Generating tissue topology through remodeling of cell-cell adhesions. Exp Cell Res 358:45-51
Nelson, Celeste M; Gleghorn, Jason P; Pang, Mei-Fong et al. (2017) Microfluidic chest cavities reveal that transmural pressure controls the rate of lung development. Development 144:4328-4335

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