A Correlation between Epithelial Proliferation Rates, Basement Membrane Component Localization Patterns, and Morphogenetic Potential in the Embryonic Mouse Lung

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Abstract
Lung epithelial branching morphogenesis results from a repetitive series of cleft and bud formation, a process dependent upon a complex interaction with the surrounding mesenchyme. The present study describes these cleft- and bud-forming regions as autonomous morphogenetic compartments within the embryonic day 11.5 (E11.5) mouse lung and directly correlates their identity with differences in epithelial proliferation rates and the localization pattern of specific basement membrane components. Lung buds were cultured in vitro, in two-dimensional planes, and labeled with a series of 5-bromo-2'-deoxyuridine (BrdU) pulses. Collectively, epithelial cells within actively budding regions of the bronchiolar tree demonstrated an at least 2.5-fold greater proliferation rate than those situated in the adjacent cleft-forming regions. Epithelial proliferation rates showed an inverse relationship with the degree of immunoreactivity of nidogen, laminin-1, fibronectin, and collagen IV within the underlying basement membrane. Epithelial cells dissected free from mesenchyme demonstrated cell-cell contact-dependent proliferation, thus revealing a hierarchy between mesenchymal signaling and direct epithelial cell-cell communication during branch formation. Dissection of the E11.5 bronchiolar tree into specific distalbud and interbud regions and their in vitro culture demonstrated differences in their autonomous morphogenetic potential. Tissue dissected from the distal tips of the lung continued to branch, whereas tissue dissected from immediately adjacent cleft regions seldom branched. Isolated distalbud tissue also continued to correlate regional differences in epithelial proliferation rates and immunolocalization patterns of nidogen, laminin-1, fibronectin, and collagen IV with branch formation. These results support the basement membrane remodeling hypothesis, thus connecting nidogen, collagen type IV, fibronectin, and laminin-1 localization with the molecular processes directing epithelial proliferation and supporting bud outgrowth and cleft formation/stabilization during lung morphogenesis.