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Single cell RNA-seq reveals heterogeneity and hierarchy of mouse mammary epithelia

ABSTRACT: The mammary epithelia are mainly composed of two distinct lineages, the basal and luminal cells. Due to the limitation of traditional transcriptome analysis of bulk mammary cells, the hierarchy and heterogeneity of mammary cells within these two lineages remain unclear. Hence, we have performed single cell RNA-seq on mammary epithelial cells of virgin and pregnant mice. Based on the respective gene expression profiles, we found mammary cells are highly heterogeneous and can be classified into distinct subgroups with signature markers. Besides, we identified and verified a rare CDH5+ subpopulation of basal lineage as quiescent mammary gland stem cells (MaSCs). Furthermore, knockout of Cdh5 in mouse mammary cells via CRISPR-Cas9 significantly impairs cell stemness and promotes the cell differentiation to luminal lineage. In addition, via pseudo-temporal analysis, we reconstructed the mammary epithelia developmental trajectory and revealed the relevant changes of gene expression and biological functions of mammary cells along the developmental process.

ORGANISM(S): Mus musculus

PROVIDER: GSE110371 | GEO | 2018/02/09

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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Single cell RNA-seq reveals heterogeneity and hierarchy of mouse mammary epithelia

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