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Loss of RANK signaling leads to stem cell activation in post pregnancy mammary glands

ABSTRACT: The purpose of this study was to elucidate the molecular changes of the mammary epithelium induced by luminal cell specific RANK deletion. We have characterized the phenotypic consequences of RANK deletion in the luminal lineage of the mammary epithelium, and uncovered that Rank KO luminal cells have reduced long term renewal following sucessive pregnancies. Lineage tracing analysis has demonstrated that during pregnancy 2, Rank deleted luminal cells are repleace by a wt luminal cell population, derived from the basal epithelium. We therefore decided to perform RNA seq in resting mammary glands from virgin and parous (following pregnancy one) females, cells were FACS sorted based on the traditional markers CD24 and CD49f and in the case of luminal cells GFP (recombined cells). We have isolated luminal cells to identify the molecular pathways involved in reduced long term renewal oberved in the parous context; basal cells were isolated to adress the putative mechanims regulated the bipotency observed during second pregnancy

ORGANISM(S): Mus musculus

PROVIDER: GSE199746 | GEO | 2023/09/01

REPOSITORIES: GEO

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LPA receptor activity is basal specific and coincident with early pregnancy and involution during mammary gland postnatal development

Project description:During pregnancy, luminal and basal epithelial cells of the adult mammary gland proliferate and differentiate resulting in remodeling of the adult gland. While pathways that control this process have been characterized in the gland as a whole, the contribution of specific cell subtypes, in particular the basal compartment, remains largely unknown. Basal cells provide structural and contractile support, however they also orchestrate the communication between the stroma and the luminal compartment at all developmental stages. Using RNA-seq, we show that basal cells are extraordinarily transcriptionally dynamic throughout pregnancy when compared to luminal cells. We identified gene expression changes that define specific basal functions acquired during development that led to the identification of novel markers. Enrichment analysis of gene sets from 24 mouse models for breast cancer pinpoint to a potential new function for insulin-like growth factor 1 (Igf1r) in the basal epithelium during lactogenesis. We establish that β-catenin signaling is activated in basal cells during early pregnancy, and demonstrate that this activity is mediated by lysophosphatidic acid receptor 3 (Lpar3). These findings identify novel pathways active during functional maturation of the adult mammary gland.

2016-10-21 | GSE88984 | GEO

10X Genomics scRNA-seq profiling of mammary gland cells from mice at different life stages

Project description:Background: Heterogeneity within the mouse mammary epithelium has been recently explored by single-cell RNA profiling. To further understand how cellular diversity changes during mammary development, we profiled single cells from different developmental stages including late embryogenesis, early postnatal, prepuberty, resting adult, mid-pregnancy, late-pregnancy, lactation and post-involution. We also compared the transcriptomes and chromatin accessibility of micro-dissected ducts versus terminal endbuds (TEBs) to help decipher the molecular properties of these specialized units that drive morphogenesis. Results: The single cell transcriptomes of 110,726 cells isolated from different stages were determined on the 10x Chromium platform and integrative analyses were performed to compare specific time-points. The mammary rudiment at E18.5 aligned more closely with the basal than the luminal lineage, while prepubertal epithelial cells at 2 weeks exhibited lineage segregation but to a less differentiated state than their adult counterparts. Integrated analysis of five stages spanning the pregnancy cycle revealed a novel alveolar progenitor that arises in late-pregnancy and stage-specific expression profiles. A continuum of states was uncovered along the basal-luminal progenitor cell axis following interrogation with >3,200 lineage-specific signature genes. Finally, exploration of micro-dissected TEBs and ducts showed that luminal cells within TEBs harbored intermediate expression profiles, and that ductal basal cells exhibited a higher level of accessible chromatin than their counterparts in TEBs.

2021-07-02 | GSE164017 | GEO

Identifying dormant Nfatc1-marked stem/progenitor cells as an important contributor for mammary lobuloalveoli formation

Project description:The Mammary gland undergoes complicated epithelial remodeling to form lobuloalveoli during pregnancy, in which basal epithelial cells remarkably increase to form a basket-like architecture. However, it remains largely unknown how dormant mammary basal stem/progenitor cells involve in lobuloalveolar development. Here, we show that Nfatc1 expression marks a rare population of mammary epithelial cells with the majority being basal epithelial cells. Nfatc1 reporter-marked basal epithelial cells are relatively dormant mammary stem/progenitor cells. Although Nfatc1 reporter-marked basal epithelial cells show limited contribution to the homeostasis of mammary epithelium, they divide rapidly during pregnancy and contribute to lobuloalveolar development. Furthermore, Nfatc1 reporter-marked basal epithelial cells are preferentially used for multiple pregnancies. Using single-cell RNA-seq analysis, we identify multiple functionally distinct clusters within the Nfatc1 reporter-marked cell-derived progeny cells during pregnancy. Taken together, our findings underscore Nfatc1 reporter-marked basal cells as dormant stem/progenitor cells that contribute to mammary lobuloalveolar development during pregnancy.

2022-02-18 | GSE175432 | GEO

Inhibitor of Differentiation 4 (ID4) represses myoepithelial differentiation of mammary stem cells through its interaction with HEB

Project description:Differentiation of stem cells embedded within the mammary epithelium is orchestrated by lineage-specifying transcription factors. Unlike the well-defined luminal hierarchy, dissection of the basal lineage has been hindered by a lack of specific markers. Inhibitor of Differentiation 4 (ID4) is a basally-restricted helix-loop-helix (HLH) transcription factor essential for mammary development. Here we show that ID4 is highly expressed in basal stem cells and decreases during myoepithelial differentiation. By integrating transcriptomic, proteomic and chromatin-association data we reveal that ID4 is required to suppress myoepithelial gene expression and cell fate.

2021-01-25 | PXD017517 | Pride

scRNA-seq analysis of human mammary epithelial cells derived from non-lactating breast tissue or from milk

Project description:Breast cancer risk is influenced by parity in an age-dependant manner, however human tissue remodelling induced by pregnancy and lactation is not well understood. In most cases, it is difficult to acquire human breast tissue during these key stages of development. Here, we present an approach to overcome this using single-cell RNA sequencing to examine viable primary mammary epithelial cells isolated from human milk (n=4) compared to resting, non-lactating human breast tissue (n=4). Overall, we examined 54,323 viable high-quality cells from mixed age and parous individuals consisting of 29,078 lactation derived mammary cells (LMCs) and 25,245 non-lactation derived mammary cells (NMCs). We identified all documented mammary subpopulations within our breast tissue samples and found that milk contains distinct secretory luminal cells together with myeloid and lymphocytic hematopoietic lineage cells. Comparing the luminal transcriptional profiles of cells isolated from the resting and lactating state identified differences in mammary cell function and metabolism between these maturation states. In future this data may be used to provide an insight into how parity influences human luminal cell metabolism and breast cancer risk.

2021-12-10 | E-MTAB-9841 | biostudies-arrayexpress

Pregnancy-associated alterations in DNA methylation patterns of mammary epithelial stem cells [reproductive stages]

Project description:Mammary gland development and luminal differentiation occur largely postnatally during puberty and pregnancy. We found that pregnancy had the most significant effects on stem cells, inducing a distinct epigenetic state that remained stable through life. Mammary glands were collected from different reproductive stages to purify different epithelium cell types, which were used for RNA extraction and hybridization on Affymetrix microarrays.

2015-01-22 | E-GEOD-54147 | biostudies-arrayexpress

Effect of laminin adhesion on basal human mammary epithelial cells

Project description:Mammary epithelium is composed by luminal and basal epithelial cells, which are adhere to the basement membrane (BM). To dissect how basal cell functions are regulated by BM laminin adhesion, we performed RNA sequencing of basal human mammary epithelial cells adhered on laminin-111, -421 or -521 coated cell culture plates for 48 hours.

2022-11-07 | GSE197950 | GEO

microRNA expression during ovine adult mammary gland development

Project description:The mammary gland undergoes extensive remodeling between the begin- ning of pregnancy and lactation; this involves cellular processes including cell proliferation, differentiation, and apoptosis, all of which are under the control of numerous regulators. To unravel the role played by miRNA, we describe here 47 new ovine miRNA cloned from mammary gland in early pregnancy displaying strong similari- ties with those already identified in the cow, human, or mouse. A microarray study of miRNA variations in the adult ovine mammary gland during pregnancy and lactation showed that 100 miRNA are regulated according to three principal patterns of expression: a de- crease in early pregnancy, a peak at midpregnancy, or an increase throughout late pregnancy and lactation. One miRNA displaying each pattern (miR-21, miR-205, and miR-200b) was analyzed by qRT- PCR. Variations in expression were confirmed for all three miRNA. Using in situ hybridization, we detected both miR-21 and miR-200 in luminal mammary epithelial cells when expressed, whereas miR-205 was expressed in basal cells during the first half of pregnancy and then in luminal cells during the second half. We therefore conclude that miR-21 is strongly expressed in the luminal cells of the normal mammary gland during early pregnancy when extensive cell prolif- eration occurs. In addition, we show that miR-205 and miR-200 are coexpressed in luminal cells, but only during the second half of pregnancy. These two miRNA may cooperate to maintain epithelial status by repressing an EMT-like program, to achieve and preserve the secretory phenotype of mammary epithelial cells. 5 samples for sheep and 5 samples for mouse

2013-01-04 | E-GEOD-32654 | biostudies-arrayexpress

Defining the Genomic Signature of the Parous Breast

Project description:It is widely accepted that a womanâs lifetime risk of developing breast cancer at menopause is reduced by early full term pregnancy and multiparity. This phenomenon is associated with the development and differentiation of the breast, which ultimately imprints a specific genomic profile in the mammary epithelium. In the present work we demonstrate that this profile represents a permanent signature that could be associated with the breast cancer risk reduction conferred by pregnancy. We have compared the gene expression profile of normal breast biopsies performed in 71 parous (P) and 42 nulliparous (NP) postmenopausal women. All samples were hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays. We compared the gene expression profile of normal breast core biopsies from 71 parous (women that had a full term pregnancy) and 42 nulliparous (women that never completed a pregnancy) postmenopausal women from Sweden. All samples were hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays.

2012-10-25 | E-GEOD-26457 | biostudies-arrayexpress

RNA-seq profiling of ductal macrophages, stromal macrophages and dendritic cells from the mammary glands of virgin, pregnant, lactating and post-weaning mice

Project description:Macrophages are diverse immune cells that reside in all tissues. Although macrophages have been implicated in mammary gland function, their diversity has not been fully addressed. By exploiting high-resolution 3D imaging and flow cytometry, we have identified a unique population of tissue-resident ductal macrophages (DMs) that form a contiguous network between the luminal and basal layers of the entire mammary gland throughout post-natal development. DMs are long-lived and constantly survey the epithelium though dendrite movement based on advanced 3D intravital imaging. While they initially originate from embryonic precursors, DMs derive from monocytes as they expand during puberty. Moreover, they undergo proliferation in pregnancy to maintain complete coverage of the epithelium in lactation, where they are poised to phagocytose milk-producing cells post-lactation and facilitate remodelling. Interestingly, DMs strongly resemble mammary tumour macrophages and form a network that pervades the tumour epithelium. Thus, the mammary epithelium programs specialised resident macrophages in both physiological and tumorigenic contexts. RNA-seq profiling demonstrates that DMs have a distinct gene expression signature from stromal macrophages or mammary-resident antigen-presenting cells and that substantial expression changes occur as DMs proliferate during pregnancy and lactation. This SuperSeries is composed of the SubSeries listed below.

2022-02-26 | GSE197493 | GEO

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