**3. Structure of fully developed mammary gland**

Fully developed mammary gland is created by two compartments: epithelial and stromal. The epithelial compartment, termed parenchyma, is composed of the branching network of ducts and lobuloalveolar structures comprised of mammary epithelial cells of two primary lineages: myoepithelial (basal) cells and epithelial (luminal) cells, forming a bilayered structure, which is embedded in the stroma [12]. Mammary ducts consist of apically orientated luminal epithelial cells that line ducts with alveolar structures at the ends and of basally orientated myoepithelial cells surrounded by a laminin and collagen-rich basement membrane (BM). Luminal epithelial cells are separated from all kinds of stromal cells, laying on top of myoepithelial cells. The functionally distinct basal layer contains myoepithelial cells with contractile properties and cells with demonstrated stem cell activity, referred as mammary repopulating units (MRUs). These cells have an ability to regenerate the bilayered glandular structure of inner luminal and basal outer epithelial cells [12]. The myoepithelial and stromal cells produce the basement membrane, which is a thin sheet composed of collagen IV, laminins, entactin, and proteoglycans, and forms physical barrier separating the epithelial and stromal compartments [3]. The stromal compartment is composed of two mesenchymal lineages: adipocytes and fibroblasts, as well as infiltrating immune and vascular endothelial cells [5]. These cells synthesize extracellular matrix (ECM) components essential for three-dimensional microstructure of the stroma. Stromal ECM components include collagens, which are the major structural proteins, as well as proteoglycans, hyaluronic acid, fibronectins, and tenascins [13, 14] (**Figure 1**).

volume and exerts a dominant effect on tissue morphogenesis. Ratio between stromal and epithelial compartment changes at all stages of mammary gland development, still staying in its own harmony milieu. Stromal cells architecturally support the epithelium, providing structure, nutrients, blood, and immune defense. Large amount of data suggest that the mammary stroma not only provides a scaffold but also regulates mammary epithelial cells (MECs) function via paracrine, physical, and reciprocal signaling between MECs and underlying stromal cells, modifying proliferation, survival, polarity, differentiation, and invasive capacity of the mammary epithelium [4, 15]. The importance of stromal cells is reflected by the fact that signals emitted by embryonic mesenchyme dictate the differentiation of epithelial cells, and mammary epithelial cells form salivary gland-like structures when placed on top of salivary gland mesenchyme [16]. On the other hand, outgrowth of salivary epithelium in contact with mammary mesenchyme resembles a mammary gland ductal tree and responds to hormonal stimuli [16]. The following paragraphs of this chapter present the complex interactions between the mammary epithelium and different stromal cells that direct the progression of

Stromal-Epithelial Interactions during Mammary Gland Development

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Adipocytes constitute the most abundant type of cells within the stroma of the mammary gland. Fat cells predominate in the stromal compartment of the mammary glands of rodents (mice and rats), whereas in the mammary glands of humans and ruminants adipocytes of white adipose tissue form the structure of a fibrous-adipose stroma along with fibroblasts. Adipocytes create a specific microenvironmental niche for MECs as the source of triglycerides and thus a source of energy, as well as a scaffold liable to invade, and a supply of various

Adipose tissue modulates epithelial development, remodeling, and function in a statedependent manner. During embryonic morphogenesis, the fat pad together with the fibroblastic mesenchyme appears before ectoderm cell migration, creating environment and scaffold for mammary buds development. At this stage, each type of mesenchymal cells has different properties. It has been shown that fat pad mesenchyme induces elongation and branching of the mammary epithelium [5]. Lack of white adipose tissue in transgenic Z-ZIP/F1 female mice leads to compromised ductal growth during prenatal development, manifested by formation of only few underdeveloped ductal structures showing severe, abnormal distension [17]. Interestingly, these transgenic Z-ZIP/F1 mice produce a mass of lobuloalveolar structures in the mammary gland during pregnancy, which suggests that interactions between MECs and adipocytes are not essential for the functional differentiation of the mammary epithelium [17]. An alternative in vivo model of adipocytes depletion (FAT-ATTAC mice) allowed scientists to explore further the role of mammary-associated adipocytes. In FAT-ATTAC mice, elimination of adipocytes can be induced at any developmental

normal mammary gland morphogenesis.

**development**

**4.1. Adipocytes**

biologically active compounds.

**4. Role of stromal cells in regulation of mammary gland** 

Stromal-epithelial interactions regulate mammary epithelial growth and differentiation during embryonic and postnatal development through soluble factors that are released into the environment, as well as through insoluble factors that are present in the stroma itself, referred as matrikines and matricryptins [14]. The stroma accounts for roughly 60% of the total tissue

**Figure 1.** Schematic representation of cells found within the structure of fully developed mammary gland. Scheme presents cross section of mammary alveolus surrounded by stromal components (cells and extracellular matrix).

volume and exerts a dominant effect on tissue morphogenesis. Ratio between stromal and epithelial compartment changes at all stages of mammary gland development, still staying in its own harmony milieu. Stromal cells architecturally support the epithelium, providing structure, nutrients, blood, and immune defense. Large amount of data suggest that the mammary stroma not only provides a scaffold but also regulates mammary epithelial cells (MECs) function via paracrine, physical, and reciprocal signaling between MECs and underlying stromal cells, modifying proliferation, survival, polarity, differentiation, and invasive capacity of the mammary epithelium [4, 15]. The importance of stromal cells is reflected by the fact that signals emitted by embryonic mesenchyme dictate the differentiation of epithelial cells, and mammary epithelial cells form salivary gland-like structures when placed on top of salivary gland mesenchyme [16]. On the other hand, outgrowth of salivary epithelium in contact with mammary mesenchyme resembles a mammary gland ductal tree and responds to hormonal stimuli [16]. The following paragraphs of this chapter present the complex interactions between the mammary epithelium and different stromal cells that direct the progression of normal mammary gland morphogenesis.
