Heterotypic cell–cell communication regulates glandular stem cell multipotency

Alessia Centonze, Shuheng Lin, Elisavet Tika, Alejandro Sifrim, Marco Fioramonti, Milan Malfait, Yura Song, Aline Wuidart, Jens Van Herck, Anne Dannau, Gaelle Bouvencourt, Christine Dubois, Nina Dedoncker, Amar Sahay, Viviane de Maertelaer, Christian W. Siebel, Alexandra Van Keymeulen, Thierry Voet and Cédric Blanpain ()
Additional contact information
Alessia Centonze: Université Libre de Bruxelles (ULB)
Shuheng Lin: Université Libre de Bruxelles (ULB)
Elisavet Tika: Université Libre de Bruxelles (ULB)
Alejandro Sifrim: University of Leuven, KU Leuven
Marco Fioramonti: Université Libre de Bruxelles (ULB)
Milan Malfait: Université Libre de Bruxelles (ULB)
Yura Song: Université Libre de Bruxelles (ULB)
Aline Wuidart: Université Libre de Bruxelles (ULB)
Jens Van Herck: University of Leuven, KU Leuven
Anne Dannau: Université Libre de Bruxelles (ULB)
Gaelle Bouvencourt: Université Libre de Bruxelles (ULB)
Christine Dubois: Université Libre de Bruxelles (ULB)
Nina Dedoncker: University of Leuven, KU Leuven
Amar Sahay: Massachusetts General Hospital
Viviane de Maertelaer: IRIBHM, Université Libre de Bruxelles (ULB)
Christian W. Siebel: Genentech
Alexandra Van Keymeulen: Université Libre de Bruxelles (ULB)
Thierry Voet: University of Leuven, KU Leuven
Cédric Blanpain: Université Libre de Bruxelles (ULB)

Nature, 2020, vol. 584, issue 7822, 608-613

Abstract: Abstract Glandular epithelia, including the mammary and prostate glands, are composed of basal cells (BCs) and luminal cells (LCs)1,2. Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells1,3–8. However, adult unipotent BSCs can reactivate multipotency under regenerative conditions and upon oncogene expression3,9–13. This suggests that an active mechanism restricts BSC multipotency under normal physiological conditions, although the nature of this mechanism is unknown. Here we show that the ablation of LCs reactivates the multipotency of BSCs from multiple epithelia both in vivo in mice and in vitro in organoids. Bulk and single-cell RNA sequencing revealed that, after LC ablation, BSCs activate a hybrid basal and luminal cell differentiation program before giving rise to LCs—reminiscent of the genetic program that regulates multipotency during embryonic development7. By predicting ligand–receptor pairs from single-cell data14, we find that TNF—which is secreted by LCs—restricts BC multipotency under normal physiological conditions. By contrast, the Notch, Wnt and EGFR pathways were activated in BSCs and their progeny after LC ablation; blocking these pathways, or stimulating the TNF pathway, inhibited regeneration-induced BC multipotency. Our study demonstrates that heterotypic communication between LCs and BCs is essential to maintain lineage fidelity in glandular epithelial stem cells.

Date: 2020
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DOI: 10.1038/s41586-020-2632-y

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