The identification and molecular characterization of cellular hierarchies in complex tissues is key to understanding both normal cellular homeostasis and tumorigenesis. The mammary epithelium is a heterogeneous tissue consisting of two main cellular compartments, an outer basal layer containing myoepithelial cells and an inner luminal layer consisting of estrogen receptor-negative (ER−) ductal cells and secretory alveolar cells (in the fully functional differentiated tissue) and hormone-responsive estrogen receptor-positive (ER+) cells. Recent publications have used single-cell RNA-sequencing (scRNA-seq) analysis to decipher epithelial cell differentiation hierarchies in human and murine mammary glands, and reported the identification of new cell types and states based on the expression of the luminal progenitor cell marker KIT (c-Kit). These studies allow for comprehensive and unbiased analysis of the different cell types that constitute a heterogeneous tissue. Researchers from University Medicine Berlin and Cardiff University discuss scRNA-seq studies in the context of previous research in which mammary epithelial cell populations were molecularly and functionally characterized, and identified c-Kit+ progenitors and cell states analogous to those reported in the recent scRNA-seq studies.
Proposed model of the mammary epithelial cell-state lineage hierarchy in the postnatal gland based on lineage tracing, functional assays, scRNA-seq, and snATAC-seq
Bipotent fetal mammary stem cells (fMaSCs) are present in the embryo and become lineage-restricted after birth. In the adult gland, each lineage is maintained by its own c-Kit+ progenitor. Loss of homeostasis (e.g., injury, cell isolation, ex vivo culture, and transplantation) or tumorigenesis may trigger a wound response that leads to acquisition of multilineage potential by facultative inducible MaSCs (iMaSCs), c-Kit+ lineage-primed, and progenitor cell states. Lineage-primed c-Kit+ basal cells that express intermediate levels of luminal genes may represent a transient or intermediate population that precedes commitment to the luminal lineage28,52. Gene expression analysis suggests that an alternative route for generating ER+ cells from intermediate luminal cell states may also exist.