A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland

Shang Cai; Tomer Kalisky; Debashis Sahoo; Piero Dalerba; Weiguo Feng; Yuan Lin; Dalong Qian; Angela Kong; Jeffrey Yu; Flora Wang; Elizabeth Y. Chen; Ferenc A. Scheeren; Angera H. Kuo; Shaheen S. Sikandar; Shigeo Hisamori; Linda J. van Weele; Diane Heiser; Sopheak Sim; Jessica Lam; Stephen Quake; Michael F. Clarke

doi:10.1016/j.stem.2016.11.007

A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland

Shang Cai, Tomer Kalisky, Debashis Sahoo, Piero Dalerba, Weiguo Feng, Yuan Lin, Dalong Qian, Angela Kong, Jeffrey Yu, Flora Wang, Elizabeth Y. Chen, Ferenc A. Scheeren, Angera H. Kuo, Shaheen S. Sikandar, Shigeo Hisamori, Linda J. van Weele, Diane Heiser, Sopheak Sim, Jessica Lam, Stephen QuakeMichael F. Clarke

Research output: Contribution to journal › Article › peer-review

84 Scopus citations

Abstract

Stem cells in many tissues sustain themselves by entering a quiescent state to avoid genomic insults and to prevent exhaustion caused by excessive proliferation. In the mammary gland, the identity and characteristics of quiescent epithelial stem cells are not clear. Here, we identify a quiescent mammary epithelial cell population expressing high levels of Bcl11b and located at the interface between luminal and basal cells. Bcl11b^high cells are enriched for cells that can regenerate mammary glands in secondary transplants. Loss of Bcl11b leads to a Cdkn2a-dependent exhaustion of ductal epithelium and loss of epithelial cell regenerative capacity. Gain- and loss-of-function studies show that Bcl11b induces cells to enter the G₀ phase of the cell cycle and become quiescent. Taken together, these results suggest that Bcl11b acts as a central intrinsic regulator of mammary epithelial stem cell quiescence and exhaustion and is necessary for long-term maintenance of the mammary gland.

Original language	English
Pages (from-to)	247-260.e5
Journal	Cell Stem Cell
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2016.11.007
State	Published - 2 Feb 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Funding

We thank Dr. Mark Leid for providing Bcl11bflox/flox mice, Dr. Pentao Liu for providing Bcl11btdTomato/wt reporter mice, Dr. Roel Nusse for providing L1-Wnt3a feeder cells, and Dr. Stephen J. Elledge for providing pINDUCER constructs. We also thank Pauline Chu for the help with paraffin sections, Patty Lovelace and Jennifer Ho for management of the flow cytometry facility, and Andrew Olson for the management of the NMS Imaging Facility. We thank Stanford PAN facility for microarray analysis. This work was supported by NIH/NCI Grant 5P01 CA139490-05, NIH/NCI Grant 5U01 CA154209-04, NIH/NCI Grant 5R01 CA100225-09, Department of Defense Grant W81XWH-11-1-0287, Department of Defense/Breast Cancer Research Program (BCRP) Innovator Award W81XWH-13-1-0281, The Breast Cancer Research Foundation, the Ludwig Foundation, and California Institute of Regenerative Medicine (CIRM) Postdoctoral Fellowship 1131681-413-UZABP.

Funders	Funder number
Department of Defense/Breast	W81XWH-13-1-0281
Ludwig Foundation
NMS Imaging Facility
National Institutes of Health
U.S. Department of Defense	W81XWH-11-1-0287
National Cancer Institute	5R01 CA100225-09, 5P01 CA139490-05, U01CA154209
Breast Cancer Research Foundation
California Institute of Regenerative Medicine	1131681-413-UZABP

Keywords

quiescence
stem cell exhaustion

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10.1016/j.stem.2016.11.007

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Cai, S., Kalisky, T., Sahoo, D., Dalerba, P., Feng, W., Lin, Y., Qian, D., Kong, A., Yu, J., Wang, F., Chen, E. Y., Scheeren, F. A., Kuo, A. H., Sikandar, S. S., Hisamori, S., van Weele, L. J., Heiser, D., Sim, S., Lam, J., ... Clarke, M. F. (2017). A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland. Cell Stem Cell, 20(2), 247-260.e5. https://doi.org/10.1016/j.stem.2016.11.007

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Cai, S, Kalisky, T, Sahoo, D, Dalerba, P, Feng, W, Lin, Y, Qian, D, Kong, A, Yu, J, Wang, F, Chen, EY, Scheeren, FA, Kuo, AH, Sikandar, SS, Hisamori, S, van Weele, LJ, Heiser, D, Sim, S, Lam, J, Quake, S & Clarke, MF 2017, 'A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland', Cell Stem Cell, vol. 20, no. 2, pp. 247-260.e5. https://doi.org/10.1016/j.stem.2016.11.007

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AU - Lin, Yuan

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AU - van Weele, Linda J.

AU - Heiser, Diane

AU - Sim, Sopheak

AU - Lam, Jessica

AU - Quake, Stephen

AU - Clarke, Michael F.

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A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland

Abstract

Bibliographical note

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Keywords

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