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Reconstructing Lineage Hierarchies of Mice Uterus Epithelia Development using Single Cell Analysis

ABSTRACT: Purpose:The endometrium layer comprises of luminal and glandular epithelia that both develop from the same simple layer of fetal uterine epithelia. Mechanisms of uterine epithelial progenitor self-renewal and differentiation are unclear. Methods: This study aims to systematically analyze the molecular and cellular mechanisms of uterine epithelia development by single cell RNA-Seq Results: An integrated set of single cell transcriptomic data of uterine epithelial progenitors and their differentiated progenies is provided. Additionally, the unique molecular signatures of these cells, characterized by sequential up-regulation of specific epigenetic and metabolic activities, and activation of unique signaling pathways and transcription factors, were also investigated. Finally, a unique subpopulation of early progenitor, as well as differentiated luminal and glandular lineages were identified. A complex cellular hierarchy of uterine epithelia development was thus delineated. Conclusions: Our study therefore systematically decoded molecular markers and cellular program of uterine epithelia development that would shed lights on uterine developmental biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE98451 | GEO | 2017/06/30

SECONDARY ACCESSION(S): PRJNA385169

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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Reconstructing Lineage Hierarchies of Mice Uterus Epithelia Development using Single Cell Analysis

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