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Models of breast morphogenesis based on localization of stem cells in the developing mammary lobule.

Honeth G, Schiavinotto T, Vaggi F, Marlow R, Kanno T, Shinomiya I, Lombardi S, Buchupalli B, Graham R, Gazinska P, Ramalingam V, Burchell J, Purushotham AD, Pinder SE, Csikasz-Nagy A, Dontu G - Stem Cell Reports (2015)

Bottom Line: However, the identity of these cells is a subject of controversy and their localization in the breast epithelium is not known.In this study, we utilized a novel approach to analyze the morphogenesis of mammary lobules, by combining one-dimensional theoretical models and computer-generated 3D fractals.An increased representation of stem cells was found in smaller, less developed lobules compared to larger, more mature lobules, with marked differences in the gland of iparous versus parous women and that of BRCA1/2 mutation carriers versus non-carriers.

View Article: PubMed Central - PubMed

Affiliation: Research Oncology, King's College London School of Medicine, London SE1 9RT, UK. Electronic address: gabriella.honeth@med.lu.se.

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Examples of 1D Theoretical Models of Lobule Development Based on Cell Fate Decisions of Stem CellsThese models predict the localization and representation of stem cells within the developing lobule, rate of growth, as well as differentiation and proliferation patterns. Two examples are shown. More models are shown in Figure S1D. Each line indicates one generation of cell divisions. Colors of cells indicate differentiation status and numbers on cells indicate if they are identical daughters. The 2D trees to the right show cell disposition in the branching lobule.(A) A model where stem cells undergo asymmetric self-renewal at a low rate of division, with proximal orientation of the most undifferentiated progeny cell (model A1B1C2 in Figure S1D). This model predicts a continuous gradient of proliferation and differentiation along the growing lobule, with the most undifferentiated cells concentrated at the base of the developing structure.(B) A model where stem cells undergo asymmetric self-renewal at a high rate of division, with distal orientation of the most undifferentiated progeny cell (model A1B2C1 in Figure S1D). This model predicts a repetitive pattern of proliferation and differentiation along the growing lobule, with the most undifferentiated cells present at the leading edge as well as at branching points.See also Figures S1 and S2.
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fig1: Examples of 1D Theoretical Models of Lobule Development Based on Cell Fate Decisions of Stem CellsThese models predict the localization and representation of stem cells within the developing lobule, rate of growth, as well as differentiation and proliferation patterns. Two examples are shown. More models are shown in Figure S1D. Each line indicates one generation of cell divisions. Colors of cells indicate differentiation status and numbers on cells indicate if they are identical daughters. The 2D trees to the right show cell disposition in the branching lobule.(A) A model where stem cells undergo asymmetric self-renewal at a low rate of division, with proximal orientation of the most undifferentiated progeny cell (model A1B1C2 in Figure S1D). This model predicts a continuous gradient of proliferation and differentiation along the growing lobule, with the most undifferentiated cells concentrated at the base of the developing structure.(B) A model where stem cells undergo asymmetric self-renewal at a high rate of division, with distal orientation of the most undifferentiated progeny cell (model A1B2C1 in Figure S1D). This model predicts a repetitive pattern of proliferation and differentiation along the growing lobule, with the most undifferentiated cells present at the leading edge as well as at branching points.See also Figures S1 and S2.

Mentions: Combinations of these fate choices generated eight different models for lobule growth that differed in rate of growth and differentiation, as well as in localization and representation of stem cells within the developing lobule. In Figure 1, we show two examples of different outcomes in cell disposition within the lobule generated by different combinations of cell fate decision. All of the eight models are shown in Figure S1D. Two additional cell fates were also modeled, i.e., symmetric self-renewal of stem cells accompanied by asymmetric division of progeny (example shown in Figure S1E) and symmetric cell divisions of progenitor cells (example shown in Figure S1F). Other combinations including these cell fates are not presented here because the outcome cannot be distinguished from the models shown in Figure S1D, being different only in growth rate. For the simplicity of diagrams, only the luminal cell layer is shown. The myoepithelial layer is supposed to be generated from stem cells in the same direction as luminal cells. It is formed of fewer, longer cells with uniform morphology and marker expression.


Models of breast morphogenesis based on localization of stem cells in the developing mammary lobule.

Honeth G, Schiavinotto T, Vaggi F, Marlow R, Kanno T, Shinomiya I, Lombardi S, Buchupalli B, Graham R, Gazinska P, Ramalingam V, Burchell J, Purushotham AD, Pinder SE, Csikasz-Nagy A, Dontu G - Stem Cell Reports (2015)

Examples of 1D Theoretical Models of Lobule Development Based on Cell Fate Decisions of Stem CellsThese models predict the localization and representation of stem cells within the developing lobule, rate of growth, as well as differentiation and proliferation patterns. Two examples are shown. More models are shown in Figure S1D. Each line indicates one generation of cell divisions. Colors of cells indicate differentiation status and numbers on cells indicate if they are identical daughters. The 2D trees to the right show cell disposition in the branching lobule.(A) A model where stem cells undergo asymmetric self-renewal at a low rate of division, with proximal orientation of the most undifferentiated progeny cell (model A1B1C2 in Figure S1D). This model predicts a continuous gradient of proliferation and differentiation along the growing lobule, with the most undifferentiated cells concentrated at the base of the developing structure.(B) A model where stem cells undergo asymmetric self-renewal at a high rate of division, with distal orientation of the most undifferentiated progeny cell (model A1B2C1 in Figure S1D). This model predicts a repetitive pattern of proliferation and differentiation along the growing lobule, with the most undifferentiated cells present at the leading edge as well as at branching points.See also Figures S1 and S2.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4400614&req=5

fig1: Examples of 1D Theoretical Models of Lobule Development Based on Cell Fate Decisions of Stem CellsThese models predict the localization and representation of stem cells within the developing lobule, rate of growth, as well as differentiation and proliferation patterns. Two examples are shown. More models are shown in Figure S1D. Each line indicates one generation of cell divisions. Colors of cells indicate differentiation status and numbers on cells indicate if they are identical daughters. The 2D trees to the right show cell disposition in the branching lobule.(A) A model where stem cells undergo asymmetric self-renewal at a low rate of division, with proximal orientation of the most undifferentiated progeny cell (model A1B1C2 in Figure S1D). This model predicts a continuous gradient of proliferation and differentiation along the growing lobule, with the most undifferentiated cells concentrated at the base of the developing structure.(B) A model where stem cells undergo asymmetric self-renewal at a high rate of division, with distal orientation of the most undifferentiated progeny cell (model A1B2C1 in Figure S1D). This model predicts a repetitive pattern of proliferation and differentiation along the growing lobule, with the most undifferentiated cells present at the leading edge as well as at branching points.See also Figures S1 and S2.
Mentions: Combinations of these fate choices generated eight different models for lobule growth that differed in rate of growth and differentiation, as well as in localization and representation of stem cells within the developing lobule. In Figure 1, we show two examples of different outcomes in cell disposition within the lobule generated by different combinations of cell fate decision. All of the eight models are shown in Figure S1D. Two additional cell fates were also modeled, i.e., symmetric self-renewal of stem cells accompanied by asymmetric division of progeny (example shown in Figure S1E) and symmetric cell divisions of progenitor cells (example shown in Figure S1F). Other combinations including these cell fates are not presented here because the outcome cannot be distinguished from the models shown in Figure S1D, being different only in growth rate. For the simplicity of diagrams, only the luminal cell layer is shown. The myoepithelial layer is supposed to be generated from stem cells in the same direction as luminal cells. It is formed of fewer, longer cells with uniform morphology and marker expression.

Bottom Line: However, the identity of these cells is a subject of controversy and their localization in the breast epithelium is not known.In this study, we utilized a novel approach to analyze the morphogenesis of mammary lobules, by combining one-dimensional theoretical models and computer-generated 3D fractals.An increased representation of stem cells was found in smaller, less developed lobules compared to larger, more mature lobules, with marked differences in the gland of iparous versus parous women and that of BRCA1/2 mutation carriers versus non-carriers.

View Article: PubMed Central - PubMed

Affiliation: Research Oncology, King's College London School of Medicine, London SE1 9RT, UK. Electronic address: gabriella.honeth@med.lu.se.

Show MeSH
Related in: MedlinePlus