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 #
5R21HL110335-02
Application #
8278596
Study Section
Special Emphasis Panel (ZRG1-CB-P (55))
Program Officer
Lin, Sara
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$201,250
Indirect Cost
$76,250
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Navis, Adam; Nelson, Celeste M (2016) Pulling together: Tissue-generated forces that drive lumen morphogenesis. Semin Cell Dev Biol 55:139-47
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
Varner, Victor D; Nelson, Celeste M (2016) Computational models of airway branching morphogenesis. Semin Cell Dev Biol :
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
Nerger, Bryan A; Siedlik, Michael J; Nelson, Celeste M (2016) Microfabricated tissues for investigating traction forces involved in cell migration and tissue morphogenesis. Cell Mol Life Sci :
Nelson, Celeste M (2016) On Buckling Morphogenesis. J Biomech Eng 138:021005
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
Kim, Hye Young; Pang, Mei-Fong; Varner, Victor D et al. (2015) Localized Smooth Muscle Differentiation Is Essential for Epithelial Bifurcation during Branching Morphogenesis of the Mammalian Lung. Dev Cell 34:719-26
Siedlik, Michael J; Nelson, Celeste M (2015) Regulation of tissue morphodynamics: an important role for actomyosin contractility. Curr Opin Genet Dev 32:80-5

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