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Collagen signaling and matrix stiffness regulate multipotencyin glandular epithelial stem cells in mice [bulk RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE243336 | GEO | 2024/11/12

REPOSITORIES: GEO

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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.

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Collagen signaling and matrix stiffness regulate multipotencyin glandular epithelial stem cells in mice [bulk RNA-Seq]

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