Journal
INTEGRATIVE BIOLOGY
Volume 2, Issue 9, Pages 424-434Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c0ib00040j
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Funding
- NIH [GM083997, CA128660]
- David & Lucile Packard Foundation
- Burroughs Welcome Fund
- Susan G. Komen for the Cure
- NATIONAL CANCER INSTITUTE [R21CA128660] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM083997] Funding Source: NIH RePORTER
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Spatial patterning of cell behaviors establishes the regional differences within tissues that collectively develop branched organs into their characteristic treelike shapes. Here we show that the pattern of branching morphogenesis of three-dimensional (3D) engineered epithelial tissues is controlled in part by gradients of endogenous mechanical stress. We used microfabrication to build model mammary epithelial tissues of defined geometry that branched in a stereotyped pattern when induced with growth factors. Branches initiated from sites of high mechanical stress within the tissues, as predicted numerically and measured directly using 3D traction force microscopy. Branch sites were defined by activation of focal adhesion kinase (FAK), inhibition of which disrupted morphogenesis. Stress, FAK activation, and branching were all altered by manipulating cellular contractility, matrix stiffness, intercellular cohesion and tissue geometry. These data suggest that the pattern and magnitude of mechanical stress across epithelial tissues cooperate with biochemical signals to specify branching pattern.
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