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

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

International Journal of Molecular Sciences ◽

10.3390/ijms20092357 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2357 ◽

Cited By ~ 1

Author(s):

Eunmi Lee ◽

Raziye Piranlioglu ◽

Max S. Wicha ◽

Hasan Korkaya

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mammary Gland ◽

Mammary Gland Development ◽

Mammary Epithelial ◽

Stem Cell Markers ◽

Quiescent State ◽

Mammary Stem Cells ◽

Mammary Stem ◽

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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Survival of Mammary Stem Cells in Suspension Culture: Implications for Stem Cell Biology and Neoplasia

Journal of Mammary Gland Biology and Neoplasia ◽

10.1007/s10911-005-2542-5 ◽

2005 ◽

Vol 10 (1) ◽

pp. 75-86 ◽

Cited By ~ 133

Author(s):

Gabriela Dontu ◽

Max S. Wicha

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Suspension Culture ◽

Cell Biology ◽

Stem Cell Biology ◽

Mammary Stem Cells ◽

Mammary Stem

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Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche

Science ◽

10.1126/science.aan4153 ◽

2018 ◽

Vol 360 (6396) ◽

pp. eaan4153 ◽

Cited By ~ 57

Author(s):

Rumela Chakrabarti ◽

Toni Celià-Terrassa ◽

Sushil Kumar ◽

Xiang Hang ◽

Yong Wei ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mammary Gland ◽

Notch Signaling ◽

Cross Talk ◽

Cell Function ◽

Notch Pathway ◽

Conditional Deletion ◽

Mammary Stem ◽

Cell Niche

The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.

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ID4 controls mammary stem cells and marks breast cancers with a stem cell-like phenotype

Nature Communications ◽

10.1038/ncomms7548 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 34

Author(s):

Simon Junankar ◽

Laura A. Baker ◽

Daniel L. Roden ◽

Radhika Nair ◽

Ben Elsworth ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Breast Cancers ◽

Mammary Stem Cells ◽

Mammary Stem

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Identification of a basal stem cell subpopulation in the prostate via functional, lineage tracing and single-cell RNA-seq analyses

10.1101/601872 ◽

2019 ◽

Cited By ~ 1

Author(s):

Xue Wang ◽

Haibo Xu ◽

Chaping Cheng ◽

Zhongzhong Ji ◽

Huifang Zhao ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Epithelial Cells ◽

Single Cell ◽

Basal Cell ◽

Lineage Tracing ◽

Cell Subpopulation ◽

Basal Cells ◽

Mesenchymal Transition ◽

Genetic Ablation

AbstractThe basal cell compartment in many epithelial tissues such as the prostate, bladder, and mammary gland are generally believed to serve as an important pool of stem cells. However, basal cells are heterogenous and the stem cell subpopulation within basal cells is not well elucidated. Here we uncover that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb is exclusively expressed in a prostate basal cell subpopulation based on both immunocytochemical and cell lineage tracing analysis. The Zeb1+prostate epithelial cells are multipotent prostate basal stem cells (PBSCs) that can self-renew and generate functional prostatic glandular structures with all three epithelial cell types at the single-cell level. Genetic ablation studies reveal an indispensable role for Zeb1 in prostate basal cell development. Utilizing unbiased single cell transcriptomic analysis of over 9000 mouse prostate basal cells, we find that Zeb1+basal cell subset shares gene expression signatures with both epithelial and mesenchymal cells and stands out uniquely among all the basal cell clusters. Moreover, Zeb1+epithelial cells can be detected in mouse and clinical samples of prostate tumors. Identification of the PBSC and its transcriptome profile is crucial to advance our understanding of prostate development and tumorigenesis.

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Gastrointestinal Stem Cells. III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00041.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. G189-G193 ◽

Cited By ~ 42

Author(s):

Neil D. Theise

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Progenitor Cells ◽

Cell Biology ◽

Stem Cell Niche ◽

Progenitor Cell ◽

Stem Cell Biology ◽

Cell Plasticity ◽

Self Renewal ◽

Cell Niche

This essay will address areas of liver stem/progenitor cell studies in which consensus has emerged and in which controversy still prevails over consensus, but it will also highlight important themes that inevitably should be a focus of liver stem/progenitor cell investigations in coming years. Thus concepts regarding cell plasticity, the existence of a physiological/anatomic stem cell niche, and whether intrahepatic liver stem/progenitor cells comprise true stem cells or progenitor cells (or both) will be approached in some detail.

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Stem Cells and the Differentiation Hierarchy in Mammary Gland Development

Physiological Reviews ◽

10.1152/physrev.00040.2018 ◽

2020 ◽

Vol 100 (2) ◽

pp. 489-523 ◽

Cited By ~ 15

Author(s):

Nai Yang Fu ◽

Emma Nolan ◽

Geoffrey J. Lindeman ◽

Jane E. Visvader

Keyword(s):

Stem Cells ◽

Mammary Gland ◽

Progenitor Cells ◽

Cell Fate ◽

Large Scale ◽

Mammary Epithelium ◽

Mammary Stem ◽

Stem And Progenitor Cells ◽

Intrinsic Complexity ◽

Small Pool

The mammary gland is a highly dynamic organ that undergoes profound changes within its epithelium during puberty and the reproductive cycle. These changes are fueled by dedicated stem and progenitor cells. Both short- and long-lived lineage-restricted progenitors have been identified in adult tissue as well as a small pool of multipotent mammary stem cells (MaSCs), reflecting intrinsic complexity within the epithelial hierarchy. While unipotent progenitor cells predominantly execute day-to-day homeostasis and postnatal morphogenesis during puberty and pregnancy, multipotent MaSCs have been implicated in coordinating alveologenesis and long-term ductal maintenance. Nonetheless, the multipotency of stem cells in the adult remains controversial. The advent of large-scale single-cell molecular profiling has revealed striking changes in the gene expression landscape through ontogeny and the presence of transient intermediate populations. An increasing number of lineage cell-fate determination factors and potential niche regulators have now been mapped along the hierarchy, with many implicated in breast carcinogenesis. The emerging diversity among stem and progenitor populations of the mammary epithelium is likely to underpin the heterogeneity that characterizes breast cancer.

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AP-2γ is Required for Maintenance of Pluripotent Mammary Stem Cells

10.1101/2020.06.10.107078 ◽

2020 ◽

Author(s):

Vivian W. Gu ◽

Edward Cho ◽

Dakota T. Thompson ◽

Victoria C. Cassady ◽

Nicholas Borcherding ◽

...

Keyword(s):

Stem Cells ◽

Mammary Gland ◽

Target Genes ◽

Mammary Development ◽

Conditional Knockout ◽

List Type ◽

Mammary Stem Cells ◽

Regenerative Capacity ◽

Mammary Stem ◽

Deficient Mice

SUMMARYMammary gland ductal morphogenesis depends on the differentiation of mammary stem cells (MaSCs) into basal and luminal lineages. The AP-2γ transcription factor, encoded by Tfap2c, has a central role in mammary gland development but its effect in mammary lineages and specifically MaSCs is largely unknown. Herein, we utilized an inducible, conditional knockout of Tfap2c to elucidate the role of AP-2γ in maintenance and differentiation of MaSCs. Loss of AP-2γ in the basal epithelium profoundly altered the transcriptomes and decreased the number of cells within several clusters of mammary epithelial cells, including adult MaSCs and luminal progenitors.AP-2γ regulated the expression of genes known to be required for mammary development including C/EBPβ, IκBα, and Rspo1. As a result, AP-2γ-deficient mice exhibited repressed mammary gland ductal outgrowth and inhibition of regenerative capacity. The findings demonstrate that AP-2γ is required for maintenance of pluripotent MaSCs and their ability to develop mammary gland structures.HighlightsAP-2γ-deficient mice exhibited repressed ductal outgrowth and regenerative capacityLoss of AP-2γ reduced the number of mammary stem and luminal progenitor cellsAP-2γ target genes, including C/EBPβ, IκBα, and Rspo1, regulate mammary developmentAP-2γ is required for maintenance of pluripotent mammary stem cellseTOC blurbGu, Cho and colleagues utilized a conditional knockout of Tfap2c to examine transcriptional effects of AP-2γ on mammary stem cells. Single cell analysis demonstrated that AP-2γ-deficient mice have decreased numbers of mammary stem cells and alteration of genes required for mammary development including C/EBPβ, IκBα, and Rspo1. They demonstrate that AP-2γ is necessary for maintenance of pluripotent mammary stem cells.

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