Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures.
The treelike structures of many organs, including the mammary gland, are generated by branching morphogenesis, a reiterative process of branch initiation and invasion from a preexisting epithelium. Using a micropatterning approach to control the initial three-dimensional structure of mouse mammary epithelial tubules in culture, combined with an algorithm to quantify the extent of branching, we found that the geometry of tubules dictates the position of branches. We predicted numerically and confirm experimentally that branches initiate at sites with a local minimum in the concentration of autocrine inhibitory morphogens, such as transforming growth factor-beta. These results reveal that tissue geometry can control organ morphogenesis by defining the local cellular microenvironment, a finding that has relevance to control of invasion and metastasis.
Nelson
Celeste M
CM
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Vanduijn
Martijn M
MM
Inman
Jamie L
JL
Fletcher
Daniel A
DA
Bissell
Mina J
MJ
D000465:Algorithms; D000818:Animals; D002460:Cell Line; D004058:Diffusion; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D004848:Epithelium / Q000254:growth & development; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development*; D051379:Mice; D009024:Morphogenesis; D009924:Organ Culture Techniques; D009940:Organoids / Q000166:cytology / Q000254:growth & development*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D023822:Tissue Engineering; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II