Abstract
Systemic growth and branching stimuli, and appropriate interactions with the host stroma are essential for the development of foreign epithelia in the mammary gland of immunodeficient mice. These factors were manipulated to promote and investigate the generation of representative bovine epithelial morphology in the transplanted mouse mammary stroma. The bovine mammary epithelium is unique in its commitment to rapid proliferation and high rate of differentiation. Its morphological organization within a fibrotic stroma resembles that of the human breast, and differs significantly from the rudimentary ductal network that penetrates a fatty stroma in mice. Transplantation of bovine mammary epithelial cells into the cleared mammary fat pad of NOD-SCID mice led to continuous growth of epithelial structures. Multilayered hollow spheres developed within fibrotic areas, but in contrast to mice, no epithelial organization was formed between adipocytes. The multilayered spheres shared characteristics with the heifer gland’s epithelium, including lumen size, cell proliferation, cytokeratin orientation, estrogen/progesterone receptor expression and localization, and milk protein synthesis. However, they did not extend into the mouse fat pad via ductal morphology. Pre-transplantation of fibroblasts increased the number of spheres, but did not promote extension of bovine morphology. The bovine cells preserved their fate and rarely participated in chimeric mouse–bovine outgrowths. Nevertheless, a single case of terminal ductal lobuloalveolar unit (TDLU) development was recorded in mice treated with estrogen and progesterone, implying the feasibility of this representative bovine morphology’s development. In vitro extension of these studies revealed paracrine inhibition of bovine epithelial mammosphere development by adipocytes, which was also generalized to breast epithelial mammosphere formation. The rescue of mammosphere development by fibroblast growth factor administration evidences an active equilibrium between inhibitory and supportive effects exerted by the adipose and fibrotic regions of the stroma, respectively, which determines the development of foreign epithelium.
Highlights
The mammalian mammary gland adopts a common tree-like morphology, with cyclic periods of production and regression
The morphology of the bovine gland resembles that of the human breast, in which the epithelium is generally closely associated with fibrous connective tissue [3,6,10], and branched terminal ductal lobuloalveolar units (TDLUs)—instead of the endbuds—represent the breast’s terminal epithelial unit [8]
Transplantation of dispersed bMECs into the mouse fat pad yields outgrowths that develop in confined fibrotic regions
Summary
The mammalian mammary gland adopts a common tree-like morphology, with cyclic periods of production and regression. The parenchyma of heifers develops as a ductallobular network and endbud structures are not present [9] In these contexts, the morphology of the bovine gland resembles that of the human breast, in which the epithelium is generally closely associated with fibrous connective tissue [3,6,10], and branched terminal ductal lobuloalveolar units (TDLUs)—instead of the endbuds—represent the breast’s terminal epithelial unit [8]. The morphology of the bovine gland resembles that of the human breast, in which the epithelium is generally closely associated with fibrous connective tissue [3,6,10], and branched terminal ductal lobuloalveolar units (TDLUs)—instead of the endbuds—represent the breast’s terminal epithelial unit [8] These differences may be connected to the mechanisms regulating paracrine signaling, development and cell hierarchy in the mouse, bovine and human glands, which are the focus of this study. Their expansion throughout the mouse fat pad has yet to be achieved, and the mechanism mediating the interactions with the mouse stroma has yet to be elucidated
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