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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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Representation of ALDH1A1+ Cells Is Higher in Immature Mammary Lobules(A) Localization of ALDH1A1+ cell in the mammary lobule based on comparison of virtual sections with equivalent immunostained tissue sections. Arrows, ALDH1A1+ areas; brown staining, ALDH1A3 (upper left).(B) In situ detection of ALDH1A1 (red or red-brown) in lobule types 1–3. Pictures show examples of representative lobules of each type. Arrow indicates rare ALDH1A1+ cells in lobule type 3. Scale bar, 100 μm. Representative examples from 18 different mammoplasty samples are shown.(C) Scatter plot with number of ALDH1A1+ cells in each lobule section plotted against the total cell number in the same lobule. Data combined from 18 different patient samples. Total number of lobules analyzed is 853.(D) Percentage of ALDH1A1+ cells in lobule types 1–3. Each dot represents one lobule. Error bars represent mean ± 95% confidence interval. P values between groups were calculated using one-way ANOVA with Tukey’s multiple comparisons test.See also Figure S6.
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fig5: Representation of ALDH1A1+ Cells Is Higher in Immature Mammary Lobules(A) Localization of ALDH1A1+ cell in the mammary lobule based on comparison of virtual sections with equivalent immunostained tissue sections. Arrows, ALDH1A1+ areas; brown staining, ALDH1A3 (upper left).(B) In situ detection of ALDH1A1 (red or red-brown) in lobule types 1–3. Pictures show examples of representative lobules of each type. Arrow indicates rare ALDH1A1+ cells in lobule type 3. Scale bar, 100 μm. Representative examples from 18 different mammoplasty samples are shown.(C) Scatter plot with number of ALDH1A1+ cells in each lobule section plotted against the total cell number in the same lobule. Data combined from 18 different patient samples. Total number of lobules analyzed is 853.(D) Percentage of ALDH1A1+ cells in lobule types 1–3. Each dot represents one lobule. Error bars represent mean ± 95% confidence interval. P values between groups were calculated using one-way ANOVA with Tukey’s multiple comparisons test.See also Figure S6.

Mentions: To better define the localization of ALDH1A1+ cells within the 3D structure of lobules, we compared virtual sections through fractal trees with breast tissue sections (Figure 5A). ALDH1A1+ cells appeared to be present at branching points and ends of ductules, in agreement with the model shown in Figure 1B (model A1B2C1). This is consistent with observations in the mouse mammary epithelium, where stem cells are positioned at the growing ends of ducts, in the so-called terminal end buds, which are also the nodes of subsequent branching (Kenney et al., 2001). Furthermore, evidence from a number of studies (Mani et al., 2008; Scheel et al., 2011) shows that stem cells from the normal mammary epithelium can undergo epithelial to mesenchymal transition, which enables them to migrate and invade in the surrounding matrix. All these observations are also consistent with a distal location of stem cells at the growing ends of ductules, rather than proximally, at the base of the lobule. However, lobular development occurs through simultaneous proliferation in the entire structure; therefore, lobular or ductal stem cells may be seen in a proximal position, at branching points, and at the distal ends of ductules (Ewald et al., 2008; Villadsen et al., 2007).


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)

Representation of ALDH1A1+ Cells Is Higher in Immature Mammary Lobules(A) Localization of ALDH1A1+ cell in the mammary lobule based on comparison of virtual sections with equivalent immunostained tissue sections. Arrows, ALDH1A1+ areas; brown staining, ALDH1A3 (upper left).(B) In situ detection of ALDH1A1 (red or red-brown) in lobule types 1–3. Pictures show examples of representative lobules of each type. Arrow indicates rare ALDH1A1+ cells in lobule type 3. Scale bar, 100 μm. Representative examples from 18 different mammoplasty samples are shown.(C) Scatter plot with number of ALDH1A1+ cells in each lobule section plotted against the total cell number in the same lobule. Data combined from 18 different patient samples. Total number of lobules analyzed is 853.(D) Percentage of ALDH1A1+ cells in lobule types 1–3. Each dot represents one lobule. Error bars represent mean ± 95% confidence interval. P values between groups were calculated using one-way ANOVA with Tukey’s multiple comparisons test.See also Figure S6.
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Related In: Results  -  Collection

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fig5: Representation of ALDH1A1+ Cells Is Higher in Immature Mammary Lobules(A) Localization of ALDH1A1+ cell in the mammary lobule based on comparison of virtual sections with equivalent immunostained tissue sections. Arrows, ALDH1A1+ areas; brown staining, ALDH1A3 (upper left).(B) In situ detection of ALDH1A1 (red or red-brown) in lobule types 1–3. Pictures show examples of representative lobules of each type. Arrow indicates rare ALDH1A1+ cells in lobule type 3. Scale bar, 100 μm. Representative examples from 18 different mammoplasty samples are shown.(C) Scatter plot with number of ALDH1A1+ cells in each lobule section plotted against the total cell number in the same lobule. Data combined from 18 different patient samples. Total number of lobules analyzed is 853.(D) Percentage of ALDH1A1+ cells in lobule types 1–3. Each dot represents one lobule. Error bars represent mean ± 95% confidence interval. P values between groups were calculated using one-way ANOVA with Tukey’s multiple comparisons test.See also Figure S6.
Mentions: To better define the localization of ALDH1A1+ cells within the 3D structure of lobules, we compared virtual sections through fractal trees with breast tissue sections (Figure 5A). ALDH1A1+ cells appeared to be present at branching points and ends of ductules, in agreement with the model shown in Figure 1B (model A1B2C1). This is consistent with observations in the mouse mammary epithelium, where stem cells are positioned at the growing ends of ducts, in the so-called terminal end buds, which are also the nodes of subsequent branching (Kenney et al., 2001). Furthermore, evidence from a number of studies (Mani et al., 2008; Scheel et al., 2011) shows that stem cells from the normal mammary epithelium can undergo epithelial to mesenchymal transition, which enables them to migrate and invade in the surrounding matrix. All these observations are also consistent with a distal location of stem cells at the growing ends of ductules, rather than proximally, at the base of the lobule. However, lobular development occurs through simultaneous proliferation in the entire structure; therefore, lobular or ductal stem cells may be seen in a proximal position, at branching points, and at the distal ends of ductules (Ewald et al., 2008; Villadsen et al., 2007).

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