Abstract
The mammary epithelium comprises two primary cellular lineages, but the degree of heterogeneity within these compartments and their lineage relationships during development remain an open question. Here we report single-cell RNA profiling of mouse mammary epithelial cells spanning four developmental stages in the post-natal gland. Notably, the epithelium undergoes a large-scale shift in gene expression from a relatively homogeneous basal-like program in pre-puberty to distinct lineage-restricted programs in puberty. Interrogation of single-cell transcriptomes reveals different levels of diversity within the luminal and basal compartments, and identifies an early progenitor subset marked by CD55. Moreover, we uncover a luminal transit population and a rare mixed-lineage cluster amongst basal cells in the adult mammary gland. Together these findings point to a developmental hierarchy in which a basal-like gene expression program prevails in the early post-natal gland prior to the specification of distinct lineage signatures, and the presence of cellular intermediates that may serve as transit or lineage-primed cells.
Highlights
The mammary epithelium comprises two primary cellular lineages, but the degree of heterogeneity within these compartments and their lineage relationships during development remain an open question
Mixed-lineage intermediates poised towards a luminal fate were identified in purified basal cells of the adult as well as in pubertal and pregnant mammary glands
We began by examining molecular heterogeneity in the mammary epithelium as the gland transitions from a rudimentary state in the early post-natal gland (2 weeks i.e. 14 days) to a developing tree in mid-puberty (5 weeks) and a highly branched ductal network in the adult (10 weeks) (Fig. 1a)
Summary
The mammary epithelium comprises two primary cellular lineages, but the degree of heterogeneity within these compartments and their lineage relationships during development remain an open question. Single-cell RNA-seq (scRNA-seq) analysis of cerebral cortex cells from the developing brain[9], developing heart[10], the adult mouse forebrain[11], lung epithelium[12], intestinal cells[13], olfactory neurons[14], and pancreatic cells[15] has revealed novel cellular subsets based on transcriptional and/or signaling pathways This methodology has been utilized to follow the induction of mouse embryonic fibroblasts to neuronal cells, identifying distinct intermediate stages during reprogramming[16]. Mixed-lineage intermediates poised towards a luminal fate were identified in purified basal cells of the adult as well as in pubertal and pregnant mammary glands These single-cell datasets spanning different developmental stages provide a valuable resource to decipher regulatory decisions in the mammary epithelium executed at the single-cell level
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