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• W2095144017 abstract "Notch signals mediate a wide range of activities in development and cancer. A report in this issue of Cell Stem Cell (Bouras et al., 2008Bouras T. Pal B. Vaillant F. Harburg G. Asselin-Labat M.-L. Oakes S.R. Lindeman G.J. Visvader J.E. Cell Stem Cell. 2008; 3 (this issue): 429-441Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar) demonstrates that Notch serves as a switch that controls cell fate and tissue homeostasis in mammary epithelium. Notch signals mediate a wide range of activities in development and cancer. A report in this issue of Cell Stem Cell (Bouras et al., 2008Bouras T. Pal B. Vaillant F. Harburg G. Asselin-Labat M.-L. Oakes S.R. Lindeman G.J. Visvader J.E. Cell Stem Cell. 2008; 3 (this issue): 429-441Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar) demonstrates that Notch serves as a switch that controls cell fate and tissue homeostasis in mammary epithelium. A number of studies have shown that overexpression of Notch causes mammary tumors in mouse models (Wu et al., 2007Wu F. Stutzman A. Mo Y.Y. Front. Biosci. 2007; 12: 4370-4383Crossref PubMed Scopus (43) Google Scholar). Aberrant Notch signaling is also detected in human breast cancers (Stylianou et al., 2006Stylianou S. Clarke R.B. Brennan K. Cancer Res. 2006; 66: 1517-1525Crossref PubMed Scopus (430) Google Scholar). In addition, inhibition of Notch signaling in the mouse mammary gland leads to an imbalance of basal and luminal cells (Buono et al., 2006Buono K.D. Robinson G.W. Martin C. Shi S. Stanley P. Tanigaki K. Honjo T. Hennighausen L. Dev. Biol. 2006; 293: 565-580Crossref PubMed Scopus (119) Google Scholar), suggesting that Notch signals regulate epithelial cell fate and may impact stem cell activity. In order to gain insight into the population-specific roles of Notch signals, Visvader and colleagues (Bouras et al., 2008Bouras T. Pal B. Vaillant F. Harburg G. Asselin-Labat M.-L. Oakes S.R. Lindeman G.J. Visvader J.E. Cell Stem Cell. 2008; 3 (this issue): 429-441Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar) manipulated Notch pathway activation in defined epithelial cell subpopulations. The authors employed retroviral vectors that either attenuated or constitutively activated Notch signaling and assayed for functional impact in short-term cultures as well as transplantation models. The mammary gland consists of a system of ducts, which are composed of two major cell types: luminal cells, which line the ducts and alveoli, and an outer network of contractile basal or myoepithelial cells. The epithelium undergoes dramatic changes during pregnancy to generate milk-producing alveolar structures. The majority of epithelial cells regresses at the end of lactation, to be restored in subsequent pregnancies, illustrating a large capacity for regeneration and self-renewal. Previous studies have established that small pieces of epithelium can redevelop an entire mammary gland from stem cells that are dispersed at discrete locations along the ductal tree. This trait forms the basis for valuable transplantation assays used to determine the functional properties of purified and/or modified epithelial cell populations, as discussed below. In recent years, three distinct fractions of epithelial cells have been isolated that reflect a hierarchical relationship within the mammary gland (Figure 1A). One population is able to regenerate an entire ductal system upon transplantation and is considered to be highly enriched in stem cells. However, cells in this fraction also express the transcription factor p63, cytokeratin 5, and smooth muscle actin, all characteristic of mature myoepithelial cells. The other two fractions both express luminal-type cytokeratins. One population, termed mammary colony-forming cells, represents a progenitor subset, based on the ability to form milk-producing colonies when grown in three-dimensional culture. The final fraction of cells contains more mature, differentiated luminal cells and does not form outgrowths or colonies (Shackleton et al., 2006Shackleton M. Vaillant F. Simpson K.J. Stingl J. Smyth G.K. Asselin-Labat M.L. Wu L. Lindeman G.J. Visvader J.E. Nature. 2006; 439: 84-88Crossref PubMed Scopus (1506) Google Scholar, Stingl et al., 2006Stingl J. Eirew P. Ricketson I. Shackleton M. Vaillant F. Choi D. Li H.I. Eaves C.J. Nature. 2006; 439: 993-997Crossref PubMed Scopus (1182) Google Scholar). The Notch pathway is initiated when two sets of transmembrane proteins (Notch receptors and Delta or Jagged family ligands) bind and activate a transcription complex that contains the cleaved Notch intracellular domain (NICD) and CBF-1 (also known as Igkjrb, RBP-Jκ, Rbpsuh). The close-range receptor-ligand relationship mediates signals between neighboring cells and has been demonstrated to impact cell lineage decisions, particularly in the central nervous system, the hematopoietic system, intestine, and skin. Expression analyses performed by Bouras et al., 2008Bouras T. Pal B. Vaillant F. Harburg G. Asselin-Labat M.-L. Oakes S.R. Lindeman G.J. Visvader J.E. Cell Stem Cell. 2008; 3 (this issue): 429-441Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar revealed varying levels of Notch ligands, receptors, and target genes present in the different mammary cell fractions. Even though target genes were most abundant in the mature subset, subtle differences in the levels of specific pathway components in each fraction probably reflect a complex regulation of Notch activities. Differential expression of Notch pathway members was also observed in transcriptome analyses of human mammary cell populations (Raouf et al., 2008Raouf A. Zhao Y. To K. Stingl J. Delaney A. Barbara M. Iscove N. Jones S. McKinney S. Emerman J. et al.Cell Stem Cell. 2008; 3: 109-118Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar). In order to dissect the specific impact of Notch signaling in the mammary lineage, the stem cell-containing population was infected with retroviral vectors expressing CBF-1 shRNA. The resulting inhibition of Notch signaling led to a slight increase in stem cell activity and increased clonogenic activity (Bouras et al., 2008Bouras T. Pal B. Vaillant F. Harburg G. Asselin-Labat M.-L. Oakes S.R. Lindeman G.J. Visvader J.E. Cell Stem Cell. 2008; 3 (this issue): 429-441Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar) (Figure 1B). In addition, in vitro cultured cells formed larger, more numerous colonies, which displayed a basal phenotype and were devoid of luminal markers. Interestingly, the center of these cultures contained concentrically layered material reminiscent of keratinized epidermal cysts, like those observed when Cbf-1 was deleted in basal cells of the epidermis (Yamamoto et al., 2003Yamamoto N. Tanigaki K. Han H. Hiai H. Honjo T. Curr. Biol. 2003; 13: 333-338Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Currently, the classification of the cysts is based solely on morphological criteria and remains to be substantiated by staining of epidermal markers. Nonetheless, the altered nature of these colonies shows a profound effect on the identity of the Notch-inhibited cells and may even indicate a switch to an epidermal fate. The ability to isolate specific cell populations and manipulate them with viral vectors permits a deconstructive approach to study genes that regulate the stem cell function. Indeed, the control of cell lineage decisions at both the stem and progenitor cell levels can be assayed in short-term cultures. This experimental system also offers a “shortcut” relative to the generation of transgenic animals (Welm et al., 2008Welm B.E. Dijkgraaf G.J. Bledau A.S. Welm A.L. Werb Z. Cell Stem Cell. 2008; 2: 90-102Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Yet, there are some caveats: first, targeting of the cells has to be efficient and specific, a drawback that applies to transgenic models as well. Furthermore, though of great value to assay immediate effects, three-dimensional culture cannot completely recapitulate the physiological conditions present in an intact animal. However, use of the transplantation assay to transfer test populations into fat pads of recipients allows the assessment of their functional capacity to generate ductal outgrowths and terminal differentiation in a pregnant host. Finally, one must not forget that some aspects of the mutual interactions between different cell lineages are lost if cell fractions are analyzed in isolation. Indeed, the use of different assay systems can lead to a range of results that may seem conflicting. For example, an opposite role for Notch in mammary stem cell function has been observed (Dontu et al., 2004Dontu G. Jackson K.W. McNicholas E. Kawamura M.J. Abdallah W.M. Wicha M.S. Breast Cancer Res. 2004; 6: R605-R615Crossref PubMed Scopus (590) Google Scholar). Using an in vitro human mammosphere culture system to assess stem cell activity and lineage commitment, the authors concluded that activation of the Notch pathway positively regulated stem cell activity and basal cell expansion. Yet the findings by Bouras et al. described above are in agreement with the observations reported by Buono et al., 2006Buono K.D. Robinson G.W. Martin C. Shi S. Stanley P. Tanigaki K. Honjo T. Hennighausen L. Dev. Biol. 2006; 293: 565-580Crossref PubMed Scopus (119) Google Scholar, who used a Cre recombinase-based genetic method to delete Cbf-1 and disrupt Notch signaling. These authors found progressive expansion of the basal cell population, particularly during the course of pregnancy. This outcome appeared to be due to increased proliferation of basal cells, combined with a luminal-to-basal fate switch, based on the presence of cells displaying a mixed phenotype, i.e., simultaneous expression of luminal cytokeratins and the basal marker p63. In the gene deletion experiment, Notch signaling was inhibited in both the basal and luminal progenitor cell populations in situ (Buono et al., 2006Buono K.D. Robinson G.W. Martin C. Shi S. Stanley P. Tanigaki K. Honjo T. Hennighausen L. Dev. Biol. 2006; 293: 565-580Crossref PubMed Scopus (119) Google Scholar), whereas Dontu et al. and Bouras et al. examined the impact of Notch signal disruption within isolated stem cell fractions. The varying results across systems most likely can be ascribed to intraepithelial regulatory interactions between basal and luminal cells, and they highlight the importance of considering the context in which stem cell function is assayed. In addition to loss-of-function experiments, Visvader and colleagues also manipulated Notch signals to achieve hyperstimulation of the pathway (Figure 1C) (Bouras et al., 2008Bouras T. Pal B. Vaillant F. Harburg G. Asselin-Labat M.-L. Oakes S.R. Lindeman G.J. Visvader J.E. Cell Stem Cell. 2008; 3 (this issue): 429-441Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar). In doing so, targeted stem cells gave rise to larger colonies of exclusively luminal cells in culture (Figure 1). Outgrowths in transplanted hosts formed hyperplastic nodules that also expressed luminal markers. Remarkably, enhancing Notch activity also endowed the luminal precursor cell pool with the potential to generate hyperplastic structures, an activity normally restricted to the more primitive, stem-cell-containing population. In vitro, the targeted progenitor cells formed anchorage-independent spheres. Combined, these observations suggest that Notch can target stem cells as well as progenitors for transformation, indicating that both populations may be considered therapeutic targets. The next challenge will be to dissect cell- and stage-specific actions of distinct Notch ligand and receptor interactions, or critical downstream target genes, in defined cell lineages. Once identified, each candidate can be assayed in three-dimensional cultures or transplantation of mixtures of individually manipulated cell fractions to understand and possibly revert transformed cells. Together, these approaches should also help generate models to direct differentiation toward a desired lineage in the mammary gland as well as other tissues. The author is supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Notch Signaling Regulates Mammary Stem Cell Function and Luminal Cell-Fate CommitmentBouras et al.Cell Stem CellOctober 09, 2008In BriefThe recent identification of mouse mammary stem cells (MaSCs) and progenitor subpopulations has enhanced the prospect of investigating the genetic control of their lineage specification and differentiation. Here we have explored the role of the Notch pathway within the mammary epithelial hierarchy. We show that knockdown of the canonical Notch effector Cbf-1 in the MaSC-enriched population results in increased stem cell activity in vivo as well as the formation of aberrant end buds, implying a role for endogenous Notch signaling in restricting MaSC expansion. Full-Text PDF Open Archive" @default.
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• W2095144017 title "Using Notches to Track Mammary Epithelial Cell Homeostasis" @default.
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