Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal 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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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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Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling

10.1101/856062 ◽

2019 ◽

Author(s):

Katerina Lawlor ◽

Maria Angeles Marques-Torrejon ◽

Gopuraja Dharmalingham ◽

Yasmine El-Azhar ◽

Michael D. Schneider ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Neural Stem Cells ◽

Cross Talk ◽

Stem Cell Niche ◽

Notch Pathway ◽

Cell Contact ◽

Cell Of Origin ◽

Wild Type ◽

Cell Niche

AbstractThere is increasing evidence suggesting that adult neural stem cells (NSCs) are a cell of origin of glioblastoma, the most aggressive form of malignant glioma. The earliest stages of hyperplasia are not easy to explore, but likely involve a cross-talk between normal and transformed NSCs. How normal cells respond to this cross-talk and if they expand or are outcompeted is poorly understood. Here we have analysed the interaction of transformed and wild-type NSCs isolated from the adult mouse subventricular zone neural stem cell niche. We find that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, however, we also demonstrate that these cells induce a quiescent-like state in surrounding wild-type NSC. We find that this response is cell-cell contact-dependent and that transformed cells activate the Notch pathway in adjacent wild-type NSCs, an event that stimulates their entry into quiescence. Our findings therefore suggest that oncogenic mutations may be propagated in the stem cell niche not just though cell-intrinsic advantages, but also by outcompeting neighbouring stem cells through signalling repression of their proliferation.

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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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Notch Signaling Regulates Mammary Stem Cell Function and Luminal Cell-Fate Commitment

Cell Stem Cell ◽

10.1016/j.stem.2008.08.001 ◽

2008 ◽

Vol 3 (4) ◽

pp. 429-441 ◽

Cited By ~ 290

Author(s):

Toula Bouras ◽

Bhupinder Pal ◽

François Vaillant ◽

Gwyndolen Harburg ◽

Marie-Liesse Asselin-Labat ◽

...

Keyword(s):

Stem Cell ◽

Notch Signaling ◽

Cell Fate ◽

Cell Function ◽

Mammary Stem Cell ◽

Luminal Cell ◽

Mammary Stem

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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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Targeting on the Stem Cell Niche Can Protect Hematopoietic Stem Cell from Chemotherapy and G-CSF

Blood ◽

10.1182/blood.v124.21.5790.5790 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5790-5790

Author(s):

Sidan Li ◽

Qiongli Zhai ◽

Dehui Zou ◽

Changhong Li ◽

Lugui Qiu

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Mouse Models ◽

Cell Function ◽

Conflicts Of Interest ◽

Hematopoietic Stem ◽

Transplant Patients ◽

Cell Engraftment ◽

Cell Niche

Abstract The majority of hematopoietic stem/progenitor cells (HSPCs) reside in the bone marrow surrounded by specialized bone-shielded environment. The specialized microenvironment or niche not only provides a favorable habitat for HSPC maintenance and development but also governs stem cell function. Here we investigated the potential role of bone remodeling osteoblasts and osteoclasts in homeostasis and stress-induced mobilization of hematopoietic progenitors, then further tested the hypothesis that targeting the niche might improve stem cell–based therapies using six mouse models to mimic the multiple rounds of chemotherapy followed by autologous hematopoietic stem cells (HSCs) transplantation in a clinical setting. Herein, we show that multiple rounds treatment of cytotoxic drugs influence niche. Serum osteocalcin level declined obviously (22.19 ± 1.08 ng/mL, before treatment vs 16.08 ± 2.12 ng/mL, steady state, P=0.01) in autologous HSPCs transplant patients. In mouse models, the number of CD45- Ter119- OPN+ osteoblast was significantly reduced (untreated, 3993 ± 129 cells/femur; CTLs, 1937 ±196 cells/femur; Gs, 1055 ± 43 cells/femur; P<0.01). Pharmacologic use of parathyroid hormone (PTH) or receptor activator of nuclear factor kappa-B ligand (RANKL) increases the number of HSC mobilized into the peripheral blood for stem cell harvests and protects stem cells from repeated exposure to cytotoxic chemotherapy. Ttreatment with granulocyte colony stimulating factor (G-CSF) plus PTH led to relative preservation of the HSC pool (G vs PTH, P<0.01; CTL vs PTH, P<0.05). Recipient mice transplanted with circulation HSPCs of P+R and P+R+G groups also showed more robust myeloid and lymphatic cell engraftment than did HSCs from either CTL or G group. These data provide evidence that targeting the HSPC niche may improve the efficacy of HSPC mobilization. Disclosures No relevant conflicts of interest to declare.

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Dietary lipids modulate Notch signaling and influence adult intestinal development and metabolism in Drosophila

10.1101/273813 ◽

2018 ◽

Cited By ~ 1

Author(s):

Rebecca Obniski ◽

Matthew Sieber ◽

Allan C. Spradling

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Notch Signaling ◽

Cell Function ◽

Dietary Cholesterol ◽

Adult Life ◽

Notch Pathway ◽

Stem Cell Differentiation ◽

Nuclear Hormone Receptor ◽

Dietary Lipids

SummaryTissue homeostasis is a complex balance of developmental signals and environmental cues that dictate stem cell function. However, it remains poorly understood how nutrients interface with developmental pathways. Using the Drosophila midgut as a model we found that during the first four days of adult life, dietary lipids including cholesterol, determine how many enteroendocrine (ee) cells differentiate and persist in the posterior midgut where lipids are preferentially absorbed. The nuclear hormone receptor Hr96 which functions to control sterol trafficking, storage, and utilization, is required for sterol-mediated changes in ee number. Dietary cholesterol influences new intestinal epithelial cell differentiation from stem cells by altering the level and persistance of Notch signaling. Exogenous lipids modulate signaling by changing the stability of the Delta ligand and Notch intracellular domain and their trafficking in endosomal vesicles. Lipid-modulated Notch signaling occurs in other nutrient-dependent tissues such as the ovary, suggesting that Delta trafficking in many cells is sensitive to cellular sterol levels. These diet-mediated alterations in ee number in young animals contribute to a metabolic program adapted to the prevailing nutrient environment that persists after the diet changes. A low sterol diet also slows the proliferation of enteroendocrine tumors initiated by disruptions in the Notch pathway. These studies show that a specific dietary nutrient can modify a key intercellular signaling pathway to shift stem cell differentiation and cause lasting changes in tissue structure and physiology.

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Canonical Notch Signaling Is Dispensable for the Maintenance of Adult Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v106.11.267.267 ◽

2005 ◽

Vol 106 (11) ◽

pp. 267-267 ◽

Cited By ~ 37

Author(s):

Ivan Maillard ◽

Seth E. Pross ◽

Olga Shestova ◽

Hong Sai ◽

Jon C. Aster ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Notch Signaling ◽

Transcriptional Activation ◽

Cell Function ◽

Fetal Life ◽

Hematopoietic Stem

Abstract Canonical Notch signaling operates through a highly conserved pathway that regulates the differentiation and homeostasis of hematopoietic cells. Ligand-receptor binding initiates proteolytic release of the Notch intracellular domain (ICN) which migrates to the nucleus, binds the transcription factor CSL/RBPJk and activates target genes through the recruitment of transcriptional coactivators of the Mastermind-like family (MAML). Notch signaling is essential for the emergence of hematopoietic stem cells (HSCs) during fetal life, but its effects on adult HSCs are controversial. In gain-of-function experiments, activation of Notch signaling in adult HSCs increased their self-renewal potential in vitro and in vivo. However, loss-of-function studies have provided conflicting results as to the role of physiological Notch signaling in HSC maintenance and homeostasis. To address this question, we expressed DNMAML1, a GFP-tagged pan-inhibitor of Notch signaling, in mouse HSCs. We have shown previously that DNMAML1 interferes with the formation of the ICN/CSL/MAML transcriptional activation complex and blocks signaling from all four Notch receptors (Notch1-4) (Maillard, Blood 2004). Transfer of DNMAML1-transduced bone marrow (BM) as compared to control GFP-transduced BM into lethally irradiated recipients gave rise to similar long-term stable expression of GFP for at least 6 months after transplant. DNMAML1 and GFP-transduced cells contributed equally to all hematopoietic lineages, except to the T cell and marginal zone B cell lineages, which are Notch-dependent. Expression of DNMAML1 did not affect the size of the BM progenitor compartment (Lin negative, Sca-1 positive, c-Kit high, or LSK cells), or the proportion of LSK cells that were negative for Flt3 and L-Selectin expression (containing long-term HSCs). The stem cell function of DNMAML1-transduced LSK cells was further assessed with in vivo competitive repopulation assays in lethally irradiated recipients. DNMAML1 and GFP-transduced LSK cells competed equally well with wild-type BM, as judged by their contribution to the myeloid lineage up to 4 months post-transplant, through two successive rounds of transplantation. Our data indicate that canonical Notch signaling is dispensable for the maintenance of stem cell function in adult HSCs.

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