The dynamics of murine mammary stem/progenitor cells

Abstract

The stem/progenitor cells in the murine mammary gland are a highly dynamic population of cells that are responsible for ductal elongation in puberty, homeostasis maintenance in adult, and lobulo-alveolar genesis during pregnancy. In recent years understanding the epithelial cell hierarchy within the mammary gland is becoming particularly important as these different stem/progenitor cells were perceived to be the cells of origin for various subtypes of breast cancer. Although significant advances have been made in enrichment and isolation of stem/progenitor cells by combinations of antibodies against cell surface proteins together with flow cytometry, and in identification of stem/progenitor cells with multi-lineage differentiation and self-renewal using mammary fat pad reconstitution assay and in vivo genetic labeling technique, a clear understanding of how these different stem/progenitors are orchestrated in the mammary gland is still lacking. Here we discuss the different in vivo and in vitro methods currently available for stem/progenitor identification, their associated caveats, and a possible new hierarchy model to reconcile various putative stem/progenitor cell populations identified by different research groups.

Aging is associated with an expansion of CD49fhi mammary stem cells that show a decline in function and increased transformation potential

“…Given the heterogeneous nature of cells in the basal population, it is difficult to discern which cell type was the main contributor to the early neoplastic lesions observed in the regenerated outgrowths derived from these old MaSCs. Although we and others have proposed possible existence of ductal and alveolar basal progenitors in the basal cell lineage [32, 33], currently there are no markers enabling the separation of these two types of basal cells. Future studies need to identify specific markers that can tag each of these distinct cell populations in the basal cell gate to allow full characterization of their roles in spontaneous tumorigenesis.…”

Characterization of mammary epithelial stem/progenitor cells and their changes with aging in common marmosets

“…These findings raise significant concern about using in vivo transplant assay as the gold standard to define stem cell property41. Although the most recent findings demonstrated the presence of multipotent MaSCs, it is generally agreeable that mammary epithelia are maintained by unipotent basal and luminal MaSCs4243.…”

“…Mammary stem cells are usually quantified using the limiting dilution in vivo transplantation assay, however, recently published lineage tracing data indicated a more restricted unipotent cell fate for MaSC tested in situ than those tested in transplantation systems 38 39 40 . These findings raise significant concern about using in vivo transplant assay as the gold standard to define stem cell property 41 . Although the most recent findings demonstrated the presence of multipotent MaSCs, it is generally agreeable that mammary epithelia are maintained by unipotent basal and luminal MaSCs 42 43 .…”

“…Although the most recent findings demonstrated the presence of multipotent MaSCs, it is generally agreeable that mammary epithelia are maintained by unipotent basal and luminal MaSCs 42 43 . Yet, current in vivo transplantation system was only able to assay basal MaSCs because luminal MaSCs (or progenitors) cannot repopulate the mammary gland in the cleared fat pad as efficiently as that of basal MaSCs 28 44 , which leaves in vitro colony forming assay the only option for luminal progenitor identification and quantification 41 . Given all these concerns, we thus mainly rely on these in vitro CFC and SFD assays for stem cell identification, which provide additional advantages over the in vivo transplantation assay as they not only allow the assessment of both basal and luminal stem/progenitors, but also are cost-effective due to no further requirement of using excessive recipient animals.…”

“…The two luminal-restricted progenitors may correspond to the ER + and ER − progenitor identified recently 44 , the myoepithelial-restricted progenitor may correspond to the unipotent basal MaSCs 40 , and the bipotent progenitor could be the multi-potent MaSCs identified recently 42 43 . Future studies are necessary to pinpoint the exact in vivo counterparts for these in vitro colonies to allow precise constructing of the stem cell hierarchy within the mammary gland 41 .…”