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Identification of Stem Cell Units in the Terminal End Bud and Duct of the Mouse Mammary Gland.

Kenney NJ, Smith GH, Lawrence E, Barrett JC, Salomon DS - J. Biomed. Biotechnol. (2001)

Bottom Line: Additionally, TUs are located every 250 +/- 75 &mgr;m in ducts or in the terminal end bud 200-600 &mgr;m in diameter.Molecules expressed in TUs were Zonula Occludens-1 and alpha-catenin proteins which were significantly detected in 75%-91% (P <0.001)of the LRCs cells that make up the TU.These data suggest that transitional units may be a group of label-retaining stem cells and maybe involved in the developmental or cancer process.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
The mouse mammary gland may undergo cycles of proliferation, terminal differentiation, tissue remodeling, and more importantly malignant transformation.Mammary epithelial stem cells and their progeny participate in these processes.Mammary epithelial stem cells are multipotent, exhibit properties of self renewal (up to 7 divisions)and may exist either as long-lived nondividing cells or as proliferating-differentiating cells. The focus of this study was to locate stem cells by identifying them as long-lived, label-retaining mammary epithelial cells (LRCs)in growth active (developing)or growth static (aged)mammary ducts. Initially, primary epithelial cells were pulse labeled with either fluorescent tracker dye and/or BrdU. Cells were then transplanted into cleared juvenile syngeneic mammary fat pads and held for 5 weeks or 8 weeks. In this study, we demonstrate that LRCs are stem cells and their progeny (transitional cells)are arranged as transitional units (TUs). Additionally, TUs are located every 250 +/- 75 &mgr;m in ducts or in the terminal end bud 200-600 &mgr;m in diameter. Molecules expressed in TUs were Zonula Occludens-1 and alpha-catenin proteins which were significantly detected in 75%-91% (P <0.001)of the LRCs cells that make up the TU. These data suggest that transitional units may be a group of label-retaining stem cells and maybe involved in the developmental or cancer process.

No MeSH data available.


Related in: MedlinePlus

Model for transitional unit operation within the mammary duct. Shortly after puberty, estrous or nursing, stem cells or transit cells (yellow) committed to acquire additional differentiation markers are positioned within the unit. Positioning (morphogenic movement) cell-cell communication (acquisition of differentiation markers), or proliferation requires modulation of α-catenin, β-catenin, ZO-1 or E-cadherin expression and cytonemes (pink). Next, accumulation of differentiation markers, β-casein and E-cadherin are acquired (blue and gray), and finally, these cells become active secretory epithelium by expressing differentiation markers such WAP (green).
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Figure 6: Model for transitional unit operation within the mammary duct. Shortly after puberty, estrous or nursing, stem cells or transit cells (yellow) committed to acquire additional differentiation markers are positioned within the unit. Positioning (morphogenic movement) cell-cell communication (acquisition of differentiation markers), or proliferation requires modulation of α-catenin, β-catenin, ZO-1 or E-cadherin expression and cytonemes (pink). Next, accumulation of differentiation markers, β-casein and E-cadherin are acquired (blue and gray), and finally, these cells become active secretory epithelium by expressing differentiation markers such WAP (green).

Mentions: How can we safely imply that such a unique structure like the TU isnot composed entirely of mammary epithelial stem cells? Earlyinvestigators have described groups of cells or aggregates as a“patterned field” [43] or as Leighton et al.[38] suggested, “a more specific biological unit” or “anaggregate may be a loosely knit, short-lived ecological unit or asupercellular living organism a distinct individual. Aggregatesmay affect one another in several ways such as adjacent cellsproviding part of the physical substrate for the migration of acell within the aggregate, or by sharing a common pool of bothsubstrates and products of metabolism.“ In line with thisrationale, previous results have indicated that nodules oraggregates from X-irradiated intestine from inactivated mosaicphosphoglycerate kinase mice(PgK-1b/PgK-1a) give rise toPgK-1b or PgK-1a absorptiveepithelial, goblet, or entero-endocrine cells [39]. Reynoldsand Weiss [40] also described that in cultures of embryonicstriatum, EGF-induced proliferation of single precursor cellsgive rise to spheres of undifferentiated cells that later divideinto three CNS cell types, neurons, astrocytes, oroligodentrocytes. In the breast, detection of clonegenicepithelium has been observed by histological assays [4] orby detection of X-chromosome inactivation, where, for example, thenormal mammary tree potentially contains contiguous patches ofclonegenic epithelium [40]. In this context, we suggest thatTUs reflect groups of transit cells with stem cells intermixedamong them. Our major argument is that although transit cells arethe direct progeny of long-lived stem cells, they cannot maintainthe same level of self-maintenance [7]. The main function oftransit cells is to progress to a more mature or differentiatedstate by acquiring one or more differentiated markers [7].In the breast, units of transit cells may operate at a programmedsite along the mammary duct or TEB by providing proliferating ordifferentiated progeny. Control of the TU is modulated by bothdifferentiated cells positioned proximal to the unit or cellularcues housed within cynonemes (Figure 6). Interestingly,units or aggregates depend on α-catenin, E-cadherin andZO-1 interactions [29, 41]. Recent data has shown that whenE-cadherin/α-catenin negative PC9 lung carcinoma cells aretransfected with α-N-catenin, single cells arrangethemselves as aggregates; patterns of closed spheres with anexpanded lumen. When these spheres are incubated withanti-E-cadherin neutralizing antibodies, the spheres completelydissociate back into single cells [37]. In this study, afluorescent labeling method was developed to visualize mammarystem cells transplanted into syngeneic fat pads. We also showthat α-catenin is expressed in stem cells and theirprogeny which together form a stem cell niche or unit that is associated with normal or aberrant breast growth. Furtherexamination of these areas using laser micro dissection isnow underway.


Identification of Stem Cell Units in the Terminal End Bud and Duct of the Mouse Mammary Gland.

Kenney NJ, Smith GH, Lawrence E, Barrett JC, Salomon DS - J. Biomed. Biotechnol. (2001)

Model for transitional unit operation within the mammary duct. Shortly after puberty, estrous or nursing, stem cells or transit cells (yellow) committed to acquire additional differentiation markers are positioned within the unit. Positioning (morphogenic movement) cell-cell communication (acquisition of differentiation markers), or proliferation requires modulation of α-catenin, β-catenin, ZO-1 or E-cadherin expression and cytonemes (pink). Next, accumulation of differentiation markers, β-casein and E-cadherin are acquired (blue and gray), and finally, these cells become active secretory epithelium by expressing differentiation markers such WAP (green).
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Related In: Results  -  Collection

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Figure 6: Model for transitional unit operation within the mammary duct. Shortly after puberty, estrous or nursing, stem cells or transit cells (yellow) committed to acquire additional differentiation markers are positioned within the unit. Positioning (morphogenic movement) cell-cell communication (acquisition of differentiation markers), or proliferation requires modulation of α-catenin, β-catenin, ZO-1 or E-cadherin expression and cytonemes (pink). Next, accumulation of differentiation markers, β-casein and E-cadherin are acquired (blue and gray), and finally, these cells become active secretory epithelium by expressing differentiation markers such WAP (green).
Mentions: How can we safely imply that such a unique structure like the TU isnot composed entirely of mammary epithelial stem cells? Earlyinvestigators have described groups of cells or aggregates as a“patterned field” [43] or as Leighton et al.[38] suggested, “a more specific biological unit” or “anaggregate may be a loosely knit, short-lived ecological unit or asupercellular living organism a distinct individual. Aggregatesmay affect one another in several ways such as adjacent cellsproviding part of the physical substrate for the migration of acell within the aggregate, or by sharing a common pool of bothsubstrates and products of metabolism.“ In line with thisrationale, previous results have indicated that nodules oraggregates from X-irradiated intestine from inactivated mosaicphosphoglycerate kinase mice(PgK-1b/PgK-1a) give rise toPgK-1b or PgK-1a absorptiveepithelial, goblet, or entero-endocrine cells [39]. Reynoldsand Weiss [40] also described that in cultures of embryonicstriatum, EGF-induced proliferation of single precursor cellsgive rise to spheres of undifferentiated cells that later divideinto three CNS cell types, neurons, astrocytes, oroligodentrocytes. In the breast, detection of clonegenicepithelium has been observed by histological assays [4] orby detection of X-chromosome inactivation, where, for example, thenormal mammary tree potentially contains contiguous patches ofclonegenic epithelium [40]. In this context, we suggest thatTUs reflect groups of transit cells with stem cells intermixedamong them. Our major argument is that although transit cells arethe direct progeny of long-lived stem cells, they cannot maintainthe same level of self-maintenance [7]. The main function oftransit cells is to progress to a more mature or differentiatedstate by acquiring one or more differentiated markers [7].In the breast, units of transit cells may operate at a programmedsite along the mammary duct or TEB by providing proliferating ordifferentiated progeny. Control of the TU is modulated by bothdifferentiated cells positioned proximal to the unit or cellularcues housed within cynonemes (Figure 6). Interestingly,units or aggregates depend on α-catenin, E-cadherin andZO-1 interactions [29, 41]. Recent data has shown that whenE-cadherin/α-catenin negative PC9 lung carcinoma cells aretransfected with α-N-catenin, single cells arrangethemselves as aggregates; patterns of closed spheres with anexpanded lumen. When these spheres are incubated withanti-E-cadherin neutralizing antibodies, the spheres completelydissociate back into single cells [37]. In this study, afluorescent labeling method was developed to visualize mammarystem cells transplanted into syngeneic fat pads. We also showthat α-catenin is expressed in stem cells and theirprogeny which together form a stem cell niche or unit that is associated with normal or aberrant breast growth. Furtherexamination of these areas using laser micro dissection isnow underway.

Bottom Line: Additionally, TUs are located every 250 +/- 75 &mgr;m in ducts or in the terminal end bud 200-600 &mgr;m in diameter.Molecules expressed in TUs were Zonula Occludens-1 and alpha-catenin proteins which were significantly detected in 75%-91% (P <0.001)of the LRCs cells that make up the TU.These data suggest that transitional units may be a group of label-retaining stem cells and maybe involved in the developmental or cancer process.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
The mouse mammary gland may undergo cycles of proliferation, terminal differentiation, tissue remodeling, and more importantly malignant transformation.Mammary epithelial stem cells and their progeny participate in these processes.Mammary epithelial stem cells are multipotent, exhibit properties of self renewal (up to 7 divisions)and may exist either as long-lived nondividing cells or as proliferating-differentiating cells. The focus of this study was to locate stem cells by identifying them as long-lived, label-retaining mammary epithelial cells (LRCs)in growth active (developing)or growth static (aged)mammary ducts. Initially, primary epithelial cells were pulse labeled with either fluorescent tracker dye and/or BrdU. Cells were then transplanted into cleared juvenile syngeneic mammary fat pads and held for 5 weeks or 8 weeks. In this study, we demonstrate that LRCs are stem cells and their progeny (transitional cells)are arranged as transitional units (TUs). Additionally, TUs are located every 250 +/- 75 &mgr;m in ducts or in the terminal end bud 200-600 &mgr;m in diameter. Molecules expressed in TUs were Zonula Occludens-1 and alpha-catenin proteins which were significantly detected in 75%-91% (P <0.001)of the LRCs cells that make up the TU. These data suggest that transitional units may be a group of label-retaining stem cells and maybe involved in the developmental or cancer process.

No MeSH data available.


Related in: MedlinePlus