Stem Cells and the Developing Mammary Gland

Abstract

The mammary gland undergoes dynamic changes throughout life. In the mouse, these begin with initial morphogenesis of the gland in the mid-gestation embryo followed by hormonally regulated changes during puberty and later in adulthood. The adult mammary gland contains a hierarchy of cell types with varying potentials for self-maintenance and differentiation. These include cells able to produce complete, functional mammary glands in vivo and that contain daughter cells with the same remarkable regenerative potential, as well as cells with more limited clonogenic activity in vitro. Here we review how applying in vitro and in vivo methods for quantifying these cells in adult mammary tissue to fetal mammary cells has enabled the first cells fulfilling the functional criteria of transplantable, isolated mammary stem cells to be identified a few days before birth. Thereafter, the number of these cells increases rapidly. Populations containing these fetal stem cells display growth and gene expression programs that differ from their adult counterparts but share signatures characteristic of certain types of breast cancer. Such observations reinforce growing evidence of important differences between tissue-specific fetal and adult cells with stem cell properties and emphasize the merits of investigating their molecular basis.

Lineage-Biased Stem Cells Maintain Estrogen-Receptor-Positive and -Negative Mouse Mammary Luminal Lineages

“…Although much progress has been made in elucidating the mammary epithelial cell hierarchy, how various luminal cell types are developed remains an unanswered question in the mammary gland field (Makarem et al, 2013; Sreekumar et al, 2015; Visvader and Stingl, 2014). It has been widely assumed that a common stem/progenitor cell population generates both ER + and ER − luminal cells, although direct experimental evidence for this is still lacking.…”

“…Each mammary gland can sustain repeated rounds of alveologenesis and involution during the reproductive period of the organism. This remarkable tissue remodeling demands robust stem/progenitor activities, and identifying the stem/progenitor cells involved in mammary development and homeostasis is a major focus of the mammary gland field (Makarem et al, 2013; Visvader and Stingl, 2014). …”

Competing views on cancer

“…Several tissues in our body present a hierarchical organization of cells ( Marshman et al 2002; Chao et al 2008; Makarem et al 2013) – the tissue-resident adult stem cells divide and generate more of their own kind (via self-renewal), and also generate committed cells ( progenitors ) that after few rounds of proliferation undergo terminal differentiation to give rise to the differentiated cells of the tissue (figure 4a). Of these various cells within a tissue, which could be the cell-of-origin of cancer that ends up accumulating the various genetic alterations proposed to be required to culminate in a successful tumour?…”

Single-cell chromatin accessibility analysis of mammary gland development reveals cell state transcriptional regulators and cellular lineage relationships

“…The mammary gland is an excellent system for studying mechanisms of cellular specification due to its accessibility, the dramatic changes it undergoes in embryogenesis and post-natal development in response to puberty, pregnancy, and involution, and the substantial knowledge gained about factors involved in these cell state transitions (Inman et al, 2015;Makarem et al, 2013;Veltmaat et al, 2003). However, there is also considerable debate on the nature of the mammary stem cells that generate and sustain the gland, and on the mechanisms for establishing the basal and luminal cell lineages (Visvader and Stingl, 2014).…”