title: A Quiescent Bcl11b High Stem Cell Population Is Required for Maintenance of the Mammary Gland.
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. Bcl11bhighcells 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 G0phase 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.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Shang
authors.initials: S
authors.lastname: Cai
authors.affiliation: Department of Bioengineering, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Tomer
authors.initials: T
authors.lastname: Kalisky
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Department of Computer Science and Engineering, University of California San Diego, San Diego, CA 92123-0984, USA.
authors.forename: Debashis
authors.initials: D
authors.lastname: Sahoo
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
authors.forename: Piero
authors.initials: P
authors.lastname: Dalerba
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA; Cancer Institute, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Feng
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA; Cancer Institute, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Dalong
authors.initials: D
authors.lastname: Qian
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Kong
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Elizabeth Y
authors.initials: EY
authors.lastname: Chen
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ferenc A
authors.initials: FA
authors.lastname: Scheeren
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Angera H
authors.initials: AH
authors.lastname: Kuo
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Shaheen S
authors.initials: SS
authors.lastname: Sikandar
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Hisamori
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: van Weele
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Heiser
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Sopheak
authors.initials: S
authors.lastname: Sim
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lam
authors.affiliation: Department of Bioengineering, School of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Quake
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA. Electronic address: mfclarke@stanford.edu.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Clarke
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002453:Cell Cycle; D019070:Cell Lineage; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D006706:Homeostasis; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012038:Regeneration / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C511143:Bcl11b protein, mouse; C493957:Cdkn1a protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins
keywords: quiescence; stem cell exhaustion