Alveolar progenitors differentiate into secretory lactocytes, also known as secretory alveolar cells (reviewed in Visvader and Stingl 2014). The availability of human-derived samples for the study of alveolar progenitors and secretory lactocytes is severely limited as these cell types are only present in pregnant and lactating women and are therefore not present in reductive mammoplasty samples that are the usual source of material to study normal adult human breast. Several recent studies have used human milk as the source of alveolar progenitors and lactocytes (Martin Carli et al. 2020, Twigger et al. 2015, Gleeson et al. 2022). While mRNA profiling of human milk-derived cells has been successful, the protein profiling of cell surface markers was shown to be challenging as cell surface markers may be lost in cells that are shed into milk (Twigger et al. 2015). Different subpopulations of lactocytes have been identified (Gleeson et al. 2022).

In mice, ectopic overexpression of the transcription factor Foxc1 suppresses lobuloalveologenesis and lactation in mice through interference with the differentiation of alveolar progenitors into lactocytes, as evidenced by markedly reduced expression of Elf5 and reduced level of activated Stat5 (Stat5a and Stat5b), an Elf5 mediator during differentiation of lactocytes (Gao et al. 2017). Based on studies in mice, Stat5 is required for expansion of hormone receptor negative luminal progenitors and alveolar progenitors, and differentiation of alveolar progenitors into lactocytes (Cui et al. 2004). Based on a mouse study, the proliferative and pro-survival signals of Stat5 in the mammary alveolar lineage may be mediated through Stat5-promoted activation of Akt signaling (Schmidt et al. 2014). Aberrantly increased Akt signaling is implicated in development of triple-negative-like breast cancer in mice from alveolar progenitor cells targeted with deletion of the Pten tumor suppressor gene, a negative regulator of Akt activation (Liu et al. 2014).

Analysis of the mouse lactating gland through three-dimensional confocal imaging of intact tissue showed that the majority of secretory alveolar cells were binucleated (Rios et al. 2016). Binucleated secretory lactocytes first arise in very late pregnancy in mice due to failure of cytokinesis that is thought to be triggered by augmented expression of AURKA and PLK1, and are larger than mononucleated cells (Rios et al. 2016). Binucleated secretory lactocytes are also prominent in lactating mammary glands in humans, seals, wallabies, and cows, suggesting that they may play an important physiological role in maximizing milk production (Rios et al. 2016).

Markers of secretory lactocytes are shown in the table below (in the table, "No" means that the marker is not listed for the specified cell type while "N/A" means that the specified cell type is not annoted in the cited external marker database):

By scRNA-seq, the two most highly expressed genes in cells isolated from fresh human milk are LALBA and CSN2, accounting for >40% of gene counts, and encoding the proteins alpha-lactalbumin and beta-casein, respectively (Gleeson et al. 2022), which are the two most abundant proteins in human milk (van Herwijnen et al. 2016).

Progesterone withdrawal following placental delivery initiates lactation, which is maintained by increased pituitary secretion of prolactin and oxytocin, and stimulated by infant suckling (reviewed in Hannan et al. 2023). The development of a human in vitro three-dimensional mammosphere model with functions similar to secretory alveoli in the mammary gland will allow more in-depth studies of lactocyte development and hormonal regulation of lactation (Watt et al. 2021). The best characterized hormone that promotes expression of milk protein genes in the mammary gland is prolactin (PRL), and it also promotes lactogenic differentiation in human mammospheres, such as expression of CSN2 (Watt et al. 2021). Among the metabolic hormones, insulin may play a crucial role in secretory differentiation and function in the mammary gland, which may explain reduced lactational efficiency in women with obesity-induced insulin resistance and gestational diabetes (Watt et al. 2021, reviewed in Hannan et al. 2023). Glucocorticoids also affect milk production (reviewed in Hannan et al. 2023).

After weaning, local cytokine production and decreased prolactin secretion trigger large-scale mammary cell loss, leading to gland involution (reviewed in Hannan et al. 2023).