Collagen signaling and matrix stiffness regulate multipotencyin glandular epithelial stem cells in mice [microarray]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE243337 | GEO | 2024/11/12
REPOSITORIES: GEO
Similar Datasets
Project description:Glandular epithelia, including mammary gland (MG) and prostate, are composed of luminal and basal cells. During embryonic development, glandular epithelia arise from multipotent stem cells (SCs) giving rise to basal and luminal cells. However, these multipotent SCs are replaced after birth by unipotent basal and unipotent luminal SCs. Different conditions, such as basal cell transplantation, luminal cell ablation, and oncogene expression, can reinduce multipotency in adult basal SC (BaSCs) of different glandular epithelia. The mechanisms regulating the reactivation of multipotency in BaSCs are incompletely understood. Here, we compared the transcriptional signature of BaSCs from MG and prostate in different conditions associated with multipotency in adult mice and uncovered that Collagen I expression was commonly upregulated across the different conditions associated with multipotency. Using MG and prostate organoids, we demonstrated that increasing collagen concentration or stiffness of the extracellular matrix (ECM) promote BaSC multipotency. Single cell RNA-seq of MG organoids in the presence of high concentration of Collagen I or in a stiffer ECM activate a hybrid bipotent state and uncovered a gene signature and signaling pathways associated with bipotent BaSCs. Finally, we demonstrated the importance of 1integrin/FAK/AP-1 axis in the regulation of BaSC multipotency in response to Col1 signaling and ECM stiffness. Altogether our study uncovers the key role of Collagen signaling and ECM stiffness in the regulation of multipotency in glandular epithelia.
2024-11-12 | GSE243336 | GEO
Project description:Glandular epithelia, including mammary gland (MG) and prostate, are composed of luminal and basal cells. During embryonic development, glandular epithelia arise from multipotent stem cells (SCs) giving rise to basal and luminal cells. However, these multipotent SCs are replaced after birth by unipotent basal and unipotent luminal SCs. Different conditions, such as basal cell transplantation, luminal cell ablation, and oncogene expression, can reinduce multipotency in adult basal SC (BaSCs) of different glandular epithelia. The mechanisms regulating the reactivation of multipotency in BaSCs are incompletely understood. Here, we compared the transcriptional signature of BaSCs from MG and prostate in different conditions associated with multipotency in adult mice and uncovered that Collagen I expression was commonly upregulated across the different conditions associated with multipotency. Using MG and prostate organoids, we demonstrated that increasing collagen concentration or stiffness of the extracellular matrix (ECM) promote BaSC multipotency. Single cell RNA-seq of MG organoids in the presence of high concentration of Collagen I or in a stiffer ECM activate a hybrid bipotent state and uncovered a gene signature and signaling pathways associated with bipotent BaSCs. Finally, we demonstrated the importance of 1integrin/FAK/AP-1 axis in the regulation of BaSC multipotency in response to Col1 signaling and ECM stiffness. Altogether our study uncovers the key role of Collagen signaling and ECM stiffness in the regulation of multipotency in glandular epithelia.
2024-11-12 | GSE243335 | GEO
Project description:Glandular epithelia including the mammary gland (MG) and the prostate are composed of basal cells (BC) and luminal cells (LC). Lineage tracing demonstrates that many glandular epithelia initially develop from multipotent basal stem cells (BaSCs) that are replaced in adult life by distinct pool of unipotent stem cells (SCs). However, adult unipotent BaSC can reactivate multipotency and give rise to LCs upon transplantation or oncogene expression, demonstrating the important plasticity of BaSCs in regenerative and pathological conditions, and suggesting that an active mechanism restricts multipotency in BaSCs during physiological conditions. The nature of this mechanism is currently unknown. Here, we assess whether basal and luminal cell-cell communication restricts multipotency in glandular epithelia. To this end, we performed lineage tracing of BCs together with the ablation of LCs in different adult glandular epithelia including MG, prostate, sweat glands and salivary glands and assessed the fate of BaSCs overtime. Interestingly, ablation of LCs reactivated multipotency in unipotent adult BaSCs from multiple epithelia. To understand the molecular mechanisms that controls multipotency in adult BaSCs, we performed population bulk-RNA-seq and single cell RNA-seq of FACS isolated adult mammary epithelial cells after LC ablation. Upon LC ablation, adult BCs activate a hybrid basal and luminal differentiation program before giving rise to LC, reminiscent of the genetic program that regulate multipotency during embryonic development. Different signaling pathways including Notch, Wnt and Egfr were activated in BaSC and their progeny following LC ablation and blocking these pathways inhibited adult BC multipotency. Altogether, our study demonstrates that heterotypic LC and BC communication is essential to maintain lineage fidelity in glandular epithelial SC during homeostasis and uncovers the lineage trajectory and signaling pathways that promote multipotency during tissue repair.
2020-04-24 | GSE127975 | GEO
Project description:Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice
| PRJNA1017844 | ENA
Project description:The mammary gland epithelium is composed of basal cells (BC) and luminal cells (LC). Lineage tracing demonstrates that many glandular epithelia initially develop from multipotent basal stem cells (BaSCs) that are replaced in adult life by distinct pool of unipotent stem cells. However, adult unipotent BaSC can reactivate multipotency and give rise to LCs upon transplantation or oncogene expression, demonstrating the important plasticity of BaSCs in regenerative and pathological conditions, and suggesting that an active mechanism restricts multipotency in BaSCs during physiological conditions. Here, we assess whether basal and luminal cell-cell communication restricts multipotency in glandular epithelia.
2020-04-23 | GSE148791 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-11-12 | GSE243338 | GEO
Project description:Collagen signaling and matrix stiffness regulate multipotency in glandular epithelial stem cells in mice [scRNA-Seq]
| PRJNA1017846 | ENA
Project description:Collagen signaling and matrix stiffness regulate multipotencyin glandular epithelial stem cells in mice [microarray]
| PRJNA1017848 | ENA
Project description:The receptor tyrosine kinase AXL is associated with epithelial plasticity in several solid tumors including breast cancer and AXL-targeting agents are currently in clinical trials. We hypothesized that AXL is a driver of stemness traits in cancer by co-option of a regulatory function normally reserved for stem cells. AXL-expressing cells in human mammary epithelial ducts co-expressed markers associated with multipotency, and AXL inhibition abolished colony-formation and self-maintenance activities while promoting terminal differentiation in vitro. Axl-null mice did not exhibit a strong developmental phenotype, but enrichment of Axl+ cells was required for mouse mammary gland reconstitution upon transplantation, and Axl-null mice had reduced incidence of Wnt1-driven mammary tumors. An AXL-dependent gene signature is a feature of transcriptomes in basal breast cancers, and reduced patient survival irrespective of subtype. Our interpretation is that AXL regulates access to epithelial plasticity programs in MaSCs and, when coopted, maintains acquired stemness in breast cancer cells.
2020-08-25 | GSE156662 | GEO
Project description:The basal cell lineage in the mouse mammary gland is perceived to be composed mostly of differentiated myoepithelial cells intermixed with a rare subpopulation of mammary stem cells. Here, we show that a high proportion (~30%) of basal cells have colony forming capacity when actin-myosin contraction is prevented. A basal cell subpopulation enriched for mammary repopulating units (MRUs) is shown to be enriched for dividing cells. Inducing basal cells to proliferate in vitro increases MRU frequency 10-fold and permits a ~750-fold expansion of MRUs. Transplantation of single-cell-derived basal colonies into cleared fat pads demonstrates that the majority (~80%) of these colonies can repopulate a mammary gland. This suggests that a high proportion of basal cells, most of which were previously perceived to be terminally differentiated myoepithelial cells, have latent mammary stem cell potential. Mammary glands from 10-14 week old, female, virgin C57BL/6J mice were dissociated into single cells and basal cells were sorted by flow cytometry at a purity of ~95%. Inducing basal cell proliferation in vitro causes mammary stem cell expansion over 7 days in culture. Basal cells were cultured on Matrigel-coated cell culture plastic in a keratinocyte stem cell media supplemented with the Rho kinase inhibitor Y-27632 and were co-seeded with irradiated NIH 3T3 fibroblast feeder cells. In order to determine the molecular changes that occur during culture that may contribute to mammary stem cell expansion, gene expression profiling was conducted on basal cells pre-culture and after 1- or 7-day-culture.
2014-06-30 | GSE31347 | GEO