Plasticity and Potency of Mammary Stem Cell Subsets During Mammary Gland Development

It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, in which the mammary stem cells (MaSC) lie at the apex with regenerative capacity as well as plasticity. Despite the fact that the majority of studies supported the existence of multipotent MaSCs giving rise to both basal and luminal lineages, others proposed lineage restricted unipotent MaSCs. Consistent with the notion, the latest research has suggested that although normal MaSC subsets mainly stay in a quiescent state, they differ in their reconstituting ability, spatial localization, and molecular and epigenetic signatures in response to physiological stimuli within the respective microenvironment during the stages of mammary gland development. In this review, we will focus on current research on the biology of normal mammary stem cells with an emphasis on properties of cellular plasticity, self-renewal and quiescence, as well as the role of the microenvironment in regulating these processes. This will include a discussion of normal breast stem cell heterogeneity, stem cell markers, and lineage tracing studies.

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3D Differentiation Of Mammosphere Derived Macaca fascicularis’s Mammary Stem Cells

Journal of Stem Cell Research and Tissue Engineering ◽

10.20473/jscrte.v3i1.16330 ◽

2019 ◽

Vol 3 (1) ◽

Author(s):

Silmi Mariya

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mammary Gland ◽

Cell Population ◽

Mammary Stem Cell ◽

Stem Cell Population ◽

Stem Cell Markers ◽

Mammary Stem Cells ◽

Surgical Biopsy ◽

Mammary Stem

The mammary gland contains adult stem cells that are capable of self-renewal. This population plays an important role in the development of mammary gland and breast cancer pathogenesis. The studies of mammary stem cells are limited due to the difficulty to acquire and expand adult stem cell population in an undifferentiated state. In this study, we developed mammosphere cultures of nulliparous cynomolgus monkeys (Macaca fascicularis; Mf) as a culture system to enrich mammary stem cells. This species has similarity of mammary gland structure as humans including anatomy, developmental stages, and lobule profile of mammary gland. The use of stem cells from primate animals is essential to bridge the knowledge gaps resulting from stem cell research using rodents for clinical trials in human. Small samples of mammary tissues were collected by surgical biopsy; cells were cultured as monolayer and cryopreserved. Cryopreserved cells were cultured into mammospheres, and the expression of markers for mammary stem cells was evaluated using qPCR. Cells were further differentiated with 3D approaches to evaluate morphology and organoid budding. The study showed that mammosphere culture resulted in an increase in the expression of mammary stem cell markers with each passage. The 3D differentiation in matrigel allowed for organoid formation. Mammary gland stem cells have been successfully differentiated which characterized by CSN2 marker expression and differentiation regulators marker STAT5 and GATA3. The results indicate that mammospheres can be successfully developed derived from breast tissue of nulliparous Mf collected via surgical biopsy. As the mammosphere allows for enrichment of mammary stem cell population, the findings also suggest that a 3-dimensional system is efficient as in-vitro model to study mammary stem cells and a useful system to study mammary differentiation in regards to cancer prevention.

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Abstract B53: Psychosocial stress exposure results in inhibition of mammary gland development and increased mammary stem cells in a rat model of breast cancer

10.1158/1538-7755.disp17-b53 ◽

2018 ◽

Author(s):

Marianna B. Johnson ◽

Joscelyn N. Hoffmann ◽

Hannah M. You ◽

Ahmad B. Allaw ◽

Jordan W. Strober ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Mammary Gland ◽

Rat Model ◽

Psychosocial Stress ◽

Mammary Gland Development ◽

Stress Exposure ◽

Mammary Stem Cells ◽

Mammary Stem ◽

Gland Development

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Stem Cells and Cellular Origins of Mammary Gland: Updates in Rationale, Controversies, and Cancer Relevance

Stem Cells International ◽

10.1155/2019/4247168 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Jiaojiao Zhou ◽

Qishan Chen ◽

Yiheng Zou ◽

Shu Zheng ◽

Yiding Chen

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mammary Gland ◽

Cell Biology ◽

Mammary Epithelium ◽

Lineage Tracing ◽

Basal Cells ◽

Mammary Stem Cells ◽

Mammary Stem ◽

Cell Niche

Evidences have supported the pivotal roles of stem cells in mammary gland development. Many molecular markers have been identified to characterize mammary stem cells. Cellular fate mapping of mammary stem cells by lineage tracing has put unprecedented insights into the mammary stem cell biology, which identified two subtypes of mammary stem cells, including unipotent and multipotent, which specifically differentiate to luminal or basal cells. The emerging single-cell sequencing profiles have given a more comprehensive understanding on the cellular hierarchy and lineage signatures of mammary epithelium. Besides, the stem cell niche worked as an essential regulator in sustaining the functions of mammary stem cells. In this review, we provide an overview of the characteristics of mammary stem cells. The cellular origins of mammary gland are discussed to understand the stem cell heterogeneity and their diverse differentiations. Importantly, current studies suggested that the breast cancer stem cells may originate from the mammary stem cells after specific mutations, indicating their close relationships. Here, we also outline the recent advances and controversies in the cancer relevance of mammary stem cells.

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Bovine mammary gland development: new insights into the epithelial hierarchy

10.1101/251637 ◽

2018 ◽

Cited By ~ 1

Author(s):

Laurence Finot ◽

Eric Chanat ◽

Frederic Dessauge

Keyword(s):

Stem Cell ◽

Mammary Gland ◽

Mammary Gland Development ◽

Mammary Epithelium ◽

Prolactin Receptors ◽

Bovine Mammary Gland ◽

Mammary Stem ◽

Gland Development ◽

Developmental Hierarchy

AbstractMilk production is highly dependent on the extensive development of the mammary epithelium, which occurs during puberty. It is therefore essential to distinguish the epithelial cells committed to development during this key stage from the related epithelial hierarchy. Using cell phenotyping and sorting, we highlighted three sub-populations that we assume to be progenitors. The CD49fhighCD24neg cells expressing KRT14, vimentin and PROCR corresponded to basal progenitors whereas the CD49flowCD24neg cells expressing luminal KRT, progesterone and prolactin receptors, were of luminal lineage. The CD49flowCD24pos cells had features of a dual lineage, with luminal and basal characteristics (CD10, ALDH1 and KRT7 expression) and were considered to be early common (bipotent) progenitors. The mammary stem cell (MaSC) fraction was recovered in a fourth sub-population of CD49fhighCD24pos cells that expressed CD10/KRT14 and KRT7. The differential ALDH1 activities observed within the MaSC fraction allowed to discriminate between two states: quiescent MaSCs and lineage-restricted “activated” MaSCs. The in-depth characterization of these epithelial sub-populations provides new insights into the epithelial cell hierarchy in the bovine mammary gland and suggests a common developmental hierarchy in mammals.

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Oleic acid stimulates HC11 mammary epithelial cells proliferation and mammary gland development in peripubertal mice through activation of CD36-Ca2+ and PI3K/Akt signaling pathway

Oncotarget ◽

10.18632/oncotarget.24204 ◽

2018 ◽

Vol 9 (16) ◽

pp. 12982-12994 ◽

Cited By ~ 5

Author(s):

Yingying Meng ◽

Jing Zhang ◽

Cong Yuan ◽

Fenglin Zhang ◽

Qin Fu ◽

...

Keyword(s):

Oleic Acid ◽

Mammary Gland ◽

Epithelial Cells ◽

Signaling Pathway ◽

Mammary Gland Development ◽

Mammary Epithelial Cells ◽

Akt Signaling ◽

Mammary Epithelial ◽

Akt Signaling Pathway ◽

Gland Development

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p19ARFDetermines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development

Molecular Biology of the Cell ◽

10.1091/mbc.e03-11-0785 ◽

2004 ◽

Vol 15 (5) ◽

pp. 2302-2311 ◽

Cited By ~ 12

Author(s):

Yijun Yi ◽

Anne Shepard ◽

Frances Kittrell ◽

Biserka Mulac-Jericevic ◽

Daniel Medina ◽

...

Keyword(s):

Cell Proliferation ◽

Mammary Gland ◽

Epithelial Cells ◽

Protein Level ◽

Normal Cell ◽

Mammary Gland Development ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Proliferation Rate ◽

Gland Development

This study demonstrated, for the first time, the following events related to p19ARFinvolvement in mammary gland development: 1) Progesterone appears to regulate p19ARFin normal mammary gland during pregnancy. 2) p19ARFexpression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19ARFprotein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19ARFin mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21Cip1and decrease in apoptosis, and 2) p19ARFnull cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21Cip1compared with WT cells. Although, p19ARFis dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19ARFnull mice, the upregulation of p19ARFby progesterone in the WT cells and the weakness of p21Cip1in mammary epithelial cells lacking p19ARFstrongly suggest that the functional role(s) of p19ARFin mammary gland development is critical to sustain normal cell proliferation rate during pregnancy and normal apoptosis in involution possibly through the p53-dependent pathway.

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An entire functional mammary gland may comprise the progeny from a single cell

Development ◽

10.1242/dev.125.10.1921 ◽

1998 ◽

Vol 125 (10) ◽

pp. 1921-1930 ◽

Cited By ~ 4

Author(s):

E.C. Kordon ◽

G.H. Smith

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mammary Gland ◽

Mammary Tumor ◽

Mouse Mammary Tumor Virus ◽

Mammary Epithelial ◽

Self Renewal ◽

Mammary Tumor Virus ◽

Mouse Mammary Tumor ◽

Tumor Virus

Any epithelial portion of a normal mouse mammary gland can reproduce an entire functional gland when transplanted into an epithelium-free mammary fat pad. Mouse mammary hyperplasias and tumors are clonal dominant populations and probably represent the progeny of a single transformed cell. Our study provides evidence that single multipotent stem cells positioned throughout the mature fully developed mammary gland have the capacity to produce sufficient differentiated progeny to recapitulate an entire functional gland. Our evidence also demonstrates that these stem cells are self-renewing and are found with undiminished capacities in the newly regenerated gland. We have taken advantage of an experimental model where mouse mammary tumor virus infects mammary epithelial cells and inserts a deoxyribonucleic acid copy(ies) of its genome during replication. The insertions occur randomly within the somatic genome. CzechII mice have no endogenous nucleic acid sequence homology with mouse mammary tumor virus; therefore all viral insertions may be detected by Southern analysis provided a sufficient number of cells contain a specific insertional event. Transplantation of random fragments of infected CzechII mammary gland produced clonal-dominant epithelial populations in epithelium-free mammary fat pads. Serial transplantation of pieces of the clonally derived outgrowths produced second generation glands possessing the same viral insertion sites providing evidence for self-renewal of the original stem cell. Limiting dilution studies with cell cultures derived from third generation clonal outgrowths demonstrated that three multipotent but distinct mammary epithelial progenitors were present in clonally derived mammary epithelial populations. Estimation of the potential number of multipotent epithelial cells that may be evolved from an individual mammary-specific stem cell by self-renewal is in the order of 10(12)-10(13). Therefore, one stem cell might easily account for the renewal of mammary epithelium over several transplant generations.

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