Local accumulation of extracellular matrix regulates global morphogenetic patterning in the developing mammary gland

• Published in: Current biology Vol. 31; no. 9; pp. 1903 - 1917.e6
• Main Authors: Nerger, Bryan A., Jaslove, Jacob M., Elashal, Hader E., Mao, Sheng, Košmrlj, Andrej, Link, A. James, Nelson, Celeste M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 10.05.2021
• Subjects: Animals; biofabrication; collective migration; Epithelium; Extracellular Matrix; finite element method; Mammary Glands, Animal; mechanical stress; mechanotransduction; Mice; morphodynamics; Morphogenesis; tissue engineering; tissue engineering; finite element method; mechanotransduction; mechanical stress; biofabrication; morphodynamics; collective migration
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2021.02.015

The tree-like pattern of the mammary epithelium is formed during puberty through a process known as branching morphogenesis. Although mammary epithelial branching is stochastic and generates an epithelial tree with a random pattern of branches, the global orientation of the developing epithelium is predictably biased along the long axis of the gland. Here, we combine analysis of pubertal mouse mammary glands, a three-dimensional (3D)-printed engineered tissue model, and computational models of morphogenesis to investigate the origin and the dynamics of the global bias in epithelial orientation during pubertal mammary development. Confocal microscopy analysis revealed that a global bias emerges in the absence of pre-aligned networks of type I collagen in the fat pad and is maintained throughout pubertal development until the widespread formation of lateral branches. Using branching and annihilating random walk simulations, we found that the angle of bifurcation of terminal end buds (TEBs) dictates both the dynamics and the extent of the global bias in epithelial orientation. Our experimental and computational data demonstrate that a local increase in stiffness from the accumulation of extracellular matrix, which constrains the angle of bifurcation of TEBs, is sufficient to pattern the global orientation of the developing mammary epithelium. These data reveal that local mechanical properties regulate the global pattern of mammary epithelial branching and may provide new insight into the global patterning of other branched epithelia. •Epithelial orientation bias emerges without aligned collagen fibers in the fat pad•The bifurcation angle of terminal end buds regulates global epithelial orientation•Local accumulation of extracellular matrix constrains the angle of bifurcation•The pattern and rate of extracellular matrix accumulation affect bifurcation angle The orientation of the developing mammary epithelium is generally thought to result from global signals within the fat pad. Nerger at al. find that the local accumulation of extracellular matrix along the flanks and at the cleft site of bifurcating terminal end buds is sufficient to regulate the global orientation of the mammary epithelium.