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Review
. 2015 May 1;401(1):103-9.
doi: 10.1016/j.ydbio.2014.12.011. Epub 2014 Dec 16.

Heterotypic control of basement membrane dynamics during branching morphogenesis

Deirdre A Nelson  1 , Melinda Larsen  2
Affiliations
Review

Heterotypic control of basement membrane dynamics during branching morphogenesis

Deirdre A Nelson et al. Dev Biol. .

Abstract

Many mammalian organs undergo branching morphogenesis to create highly arborized structures with maximized surface area for specialized organ function. Cooperative cell-cell and cell-matrix adhesions that sculpt the emerging tissue architecture are guided by dynamic basement membranes. Properties of the basement membrane are reciprocally controlled by the interacting epithelial and mesenchymal cell populations. Here we discuss how basement membrane remodeling is required for branching morphogenesis to regulate cell-matrix and cell-cell adhesions that are required for cell patterning during morphogenesis and how basement membrane impacts morphogenesis by stimulation of cell patterning, force generation, and mechanotransduction. We suggest that in addition to creating mature epithelial architecture, remodeling of the epithelial basement membrane during branching morphogenesis is also essential to promote maturation of the stromal mesenchyme to create mature organ structure. Recapitulation of developmental cell-matrix and cell-cell interactions are of critical importance in tissue engineering and regeneration strategies that seek to restore organ function.

Keywords: Branching morphogenesis; Cell–cell adhesions; Cell–matrix adhesions; Heterotypic; Mechanotransduction; Tissue engineering.

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Figures

Fig. 1
Fig. 1. Heterotypic cell contributions to basement membrane assembly
Epithelial cells produce a diverse group of basement membrane (BM) proteins (i.e. laminins, collagen IV, agrin, perlecan, etc) and other basement membrane components that are anchored to the cell membrane via integrins and other matrix receptor proteins. Mesenchymal cells, enclosed within and attached to their own ECM via integrins, synthesize some laminin and also nidogen that crosslinks laminins with collagen IV. Epithelial cell adherence to the assembled BM can be regulated by mesenchymal growth factors that activate epithelial growth factor receptors.
Fig. 2
Fig. 2. Topology and compliance of the basement membrane and extracellular matrix regulate branching morphogenesis
In developing mammary gland, cells at the tip of an epithelial end bud extend into the surrounding anisotropic ECM and undergo a local EMT. Expansion and extension of the bud is facilitated by breaks in the basement membrane, as are detected in other branching organs. In a 3D mammary model system, axially aligned anisotropic collagen I fibers are sensed by the the epithelium and stimulate ductalization while isotropic fibers facilitate acinar formation and may also facilitate bud outgrowth and EMT (dotted lines). Mesenchyme cells can align ECM and epithelial cells can also contribute to fiber alignment through Rho/ROCK pathway-mediated contraction.
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