Raouf Afshin, Zhao Yun, To Karen, Stingl John, Delaney Allen, Barbara Mary, Iscove Norman, Jones Steven, McKinney Steven, Emerman Joanne, Aparicio Samuel, Marra Marco, Eaves Connie
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
Cell Stem Cell. 2008 Jul 3;3(1):109-18. doi: 10.1016/j.stem.2008.05.018.
Mature mammary epithelial cells are generated from undifferentiated precursors through a hierarchical process, but the molecular mechanisms involved, particularly in the human mammary gland, are poorly understood. To address this issue, we isolated highly purified subpopulations of primitive bipotent and committed luminal progenitor cells as well as mature luminal and myoepithelial cells from normal human mammary tissue and compared their transcriptomes obtained using three different methods. Elements unique to each subset of mammary cells were identified, and changes that accompany their differentiation in vivo were shown to be recapitulated in vitro. These include a stage-specific change in NOTCH pathway gene expression during the commitment of bipotent progenitors to the luminal lineage. Functional studies further showed NOTCH3 signaling to be critical for this differentiation event to occur in vitro. Taken together, these findings provide an initial foundation for future delineation of mechanisms that perturb primitive human mammary cell growth and differentiation.
成熟的乳腺上皮细胞是通过一个分级过程从未分化的前体细胞产生的，但其中涉及的分子机制，尤其是在人类乳腺中，仍知之甚少。为了解决这个问题，我们从正常人乳腺组织中分离出高度纯化的原始双能和定向腔祖细胞亚群以及成熟的腔细胞和肌上皮细胞，并比较了使用三种不同方法获得的它们的转录组。确定了每个乳腺细胞亚群特有的元素，并表明它们在体内分化过程中伴随的变化在体外得以重现。这些变化包括在双能祖细胞定向分化为腔谱系过程中NOTCH信号通路基因表达的阶段特异性变化。功能研究进一步表明，NOTCH3信号对于这种分化事件在体外发生至关重要。综上所述，这些发现为未来描绘扰乱原始人类乳腺细胞生长和分化的机制提供了初步基础。
