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Single cell transcriptome atlas of mouse mammary epithelial cells across development

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posted on 09.08.2021, 23:49 by Bhupinder PalBhupinder Pal, Y Chen, MJG Milevskiy, F Vaillant, L Prokopuk, CA Dawson, BD Capaldo, X Song, F Jackling, P Timpson, GJ Lindeman, GK Smyth, JE Visvader
Background: Heterogeneity within the mouse mammary epithelium and potential lineage relationships have been recently explored by single-cell RNA profiling. To further understand how cellular diversity changes during mammary ontogeny, we profiled single cells from nine different developmental stages spanning late embryogenesis, early postnatal, prepuberty, adult, mid-pregnancy, late-pregnancy, and post-involution, as well as the transcriptomes of micro-dissected terminal end buds (TEBs) and subtending ducts during puberty. Methods: The single cell transcriptomes of 132,599 mammary epithelial cells from 9 different developmental stages were determined on the 10x Genomics Chromium platform, and integrative analyses were performed to compare specific time points. Results: The mammary rudiment at E18.5 closely aligned with the basal lineage, while prepubertal epithelial cells exhibited lineage segregation but to a less differentiated state than their adult counterparts. Comparison of micro-dissected TEBs versus ducts showed that luminal cells within TEBs harbored intermediate expression profiles. Ductal basal cells exhibited increased chromatin accessibility of luminal genes compared to their TEB counterparts suggesting that lineage-specific chromatin is established within the subtending ducts during puberty. An integrative analysis of five stages spanning the pregnancy cycle revealed distinct stage-specific profiles and the presence of cycling basal, mixed-lineage, and 'late' alveolar intermediates in pregnancy. Moreover, a number of intermediates were uncovered along the basal-luminal progenitor cell axis, suggesting a continuum of alveolar-restricted progenitor states. Conclusions: This extended single cell transcriptome atlas of mouse mammary epithelial cells provides the most complete coverage for mammary epithelial cells during morphogenesis to date. Together with chromatin accessibility analysis of TEB structures, it represents a valuable framework for understanding developmental decisions within the mouse mammary gland.

Funding

This work was supported by the Australian National Health and Medical Research Council (NHMRC), grants #1016701, #1054618, #1100807, #1113133; NHMRC IRIISS; Chan Zuckerberg Initiative EOSS; the Victorian State Government through Victoria Cancer Agency Funding and Operational Infrastructure Support; the National Breast Cancer Foundation (IIRS-20-022); the Australian Cancer Research Foundation and the Ian Potter Foundation; M.M. by VCA Fellowship ECRF19011; Y.C. by MRFF Investigator Grant #1176199; G.J.L. and G.K.S. by NHMRC Fellowships #1078730, #1058892; and J.E.V. by NHMRC Fellowships #1037230 and 1102742.

History

Publication Date

01/12/2021

Journal

Breast Cancer Research

Volume

23

Issue

1

Article Number

69

Pagination

19p.

Publisher

Springer Nature

ISSN

1465-542X

Rights Statement

The Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.