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  • When we compared the in

    2018-10-24

    When we compared the in vivo MaSC activity using the gold standard mammary fat pad transplant assay, we found the CD24+ CD49fhi SCA-1neg cells had higher stem cell activity than the CD24+ CD49fhi SCA-1+ subset. Although the stem cell activity of the CD24+ CD49fhi SCA-1+ cells was limited (in vitro mammospheres and in vivo transplants), they were able to generate all the lineages, thereby fulfilling a major requirement of an MaSC. However, they did not have progenitor activity in vitro. Our data showing that the SCA-1neg compartment has higher in vivo stem cell activity is consistent with the work of Stingl et al. (2006) and Shackleton et al. (2006) but contrasts with the work of Welm et al. (2002), who showed SCA-1 enriched for MaSCs. However, these early studies compared the SCA-1+ versus negative epithelial cell compartments without prior selection on lineage or epithelial cells and so may be complicated by the inclusion of nonepithelial cells. They were unable to calculate the stem cell enrichment, as only six transplants were completed and the cell inoculum varied. Direct comparisons in the same laboratory with numerous replicates at each dose are required to determine why these differences occur. In line with the aforementioned hypothesis that changes with the SCA-1+ subset of the CD24+ CD49fhi population with age is in response to estrogen signaling, we showed that the CD24+ CD49fhi SCA-1+ cells are mitotically active at 6 weeks of age compared with the CD24+ CD49fhi SCA-1neg cells. Interestingly, neither population has greater than 0.1% of cells in G0 of the rxr receptor at 6 weeks, indicating that like the hematopoietic system (Cheng et al., 2000), adult stem cells within the mammary gland are not dormant. ERα expression was confirmed to be significantly increased in the SCA-1+ compared with the SCA-1neg CD24+ CD49fhi population using both mRNA and protein analysis, indicating direct estrogen responsiveness. Previous studies were unable to show ERα transcripts and very limited protein in CD49fhi stem cells (Asselin-Labat et al., 2006; Sleeman et al., 2007). We propose this was a consequence of using 10- to 12-week-old mice, in which the CD24+ CD49fhi SCA-1+ subset is quite low. However, Asselin-Labat et al. (2006) did report that 0.01% of the MaSC cells that they assessed had ERα expression, and thus it may be that these rare cells were the SCA-1+ cells in the MaSC pool. As the CD24+ CD49fhi SCA-1+ cells decrease at puberty but paradoxically express ERα, it was proposed that they were negatively regulated by estrogen. This was confirmed when estrogen-deficient mouse models (Ex3αERKO, AF2ERKI, and ArKO) were assessed as adults (10–12 weeks of age) and showed a high proportion of CD24+ CD49fhi SCA-1+ cells. Adding support to this, treatment of ArKO mice with estrogen shifted the proportion of CD24+ CD49fhi SCA-1+ cells into CD24+ CD49fhi SCA-1neg cells, leading to an increase in mammary gland growth. Due to this negative regulation of SCA-1+ cells by estrogen overlapping with a period of high mitotic activity, we postulate that these CD24+CD49fhi SCA-1+ cells are important in ductal expansion of the mammary gland at puberty. To investigate this point further, lineage tracing will be required. Furthermore, since these cells are so sensitive to changes in estrogen and are in such high abundance in the young mammary gland, it implicates them in the understanding of how hormone exposure can mediate BCa risk many decades after exposure. If the CD24+ CD49fhi SCA-1+ cells are also shown to be the most carcinogen sensitive, it may explain why carcinogenic exposure in younger women has the most deleterious impact on BCa risk later in life. Intriguingly, HSCs, which are also SCA-1+, undergo more frequent self-renewing divisions in females compared with males, which Nakada et al. (2014) recently proved could be mediated by estrogen. Estrogen was also shown to be critical for the mobilization of proliferating HSCs to the spleen and expansion of splenic erythropoiesis during pregnancy (Nakada et al., 2014).