Expansion of specialized epidermis induced by hormonal state and mechanical strain

Abstract

In mammals, some sites of specialized skin such as the palms, soles, and lips grow proportionally with the animal. However, other types of specialized skin such as the nipple and anal/genital region are dramatically altered with changes of reproductive status. The specific cell types that mediate the growth of these sites have not been identified. In the mouse, we observed a dramatic expansion of the specialized epidermis of the nipple, coupled to changes in connective tissue and hair shaft density, which we designate as areola formation. During this process thymidine analog uptake was elevated in the epidermis and hair follicles. Although there were no changes in connective tissue cell proliferation, we did observe an altered expression of extracellular matrix genes. In addition, the fibroblasts of the virgin nipple areola and region showed increased transcript and protein levels for estrogen, progesterone, relaxin, and oxytocin relative to those of ventral skin. To determine the role of pregnancy, lactation hormonal milieu, and localized mechanical strain on areola formation, we created models that separated these stimuli and evaluated changes in gross structure, proliferation and protein expression. While modest increases of epidermal proliferation and remodeling of connective tissue occurred as a result of individual stimuli, areola formation required exposure to pregnancy hormones, as well as mechanical strain.

Estrogen modulates mesenchyme-epidermis interactions in the adult nipple

“…Fibroblasts associated with the mammary gland in mice have long been recognized to be responsive to estrogen (Hiremath et al, 2012;Cunha et al, 1997;Wu et al, 2015). Not surprisingly, pregnancy-and lactation-related hormone receptors, including progesterone receptor (Pgr), oxytocin receptor (Oxtr) and relaxin receptor (Rxfp1) were strongly upregulated in the nipple-like KrP fibroblasts as determined by microarray analysis (Fig.…”

“…5). The nipple expands during late pregnancy, when estrogen levels peak, and this is accompanied by high levels of nuclear Esr1 in the fibroblasts (Wu et al, 2015). This prompted us to speculate that estrogen likely triggers changes in the signaling environment required for the production and expansion of adult nipple connective tissue, and the maintenance of the unique thickened epidermis.…”

“…S5). Moreover, nipple size, which is largely controlled by the extracellular matrix (Wu et al, 2015), was ∼30% smaller in the ovexed WT mice as compared to age-matched controls, and specialized nipple connective tissue, typically composed of small tightly packed collagen bundles, was markedly diminished in the ovexed KrP mice (Fig. 5E).…”

“…Primary fibroblasts were isolated as previously described (Lichti et al, 2008;Wu et al, 2015). Briefly, ventral skin from 6-to 8-week-old female virgin WT or KrP mice was carefully dissected to remove mammary glands, and floated on 0.25% trypsin (Gibco Thermo Fisher Scientific) overnight at 4°C.…”

“…Whether the fibroblasts that underlie the nipple are simply derived from mammary mesenchyme cells remains to be determined. Nevertheless, during skin development these cells appear to have the capacity to induce and maintain the specialized epidermis that characterizes the structure (Foley et al, 2001;Wu et al, 2015).…”