Uncovering the stem cell hierarchy by genetic lineage tracing in the mammary gland

Liliana Osório; Fei Long; Zhongjun Zhou; Liliana Osório; Fei Long; Zhongjun Zhou

doi:10.3934/genet.2016.2.130

AIMS Genetics

2016, Volume 3, Issue 2: 130-145. doi: 10.3934/genet.2016.2.130

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Review

Uncovering the stem cell hierarchy by genetic lineage tracing in the mammary gland

1.
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong Hong Kong, China
2.
Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China

Received: 05 May 2016 Accepted: 07 July 2016 Published: 12 July 2016

The mammary gland is the distinct feature that gives the name to the class of mammals and distinguishes them from other animals. Functionally, the mammary gland is a secretory organ which main role is to produce milk to nourish the offspring. Organogenesis of the mammary gland starts during embryogenesis but occurs mainly after birth at puberty under the influence of hormonal cues. Throughout the adult life as well as during pregnancy, the mammary gland shows a remarkable regenerative ability, thus constituting an excellent model for studying stem cell biology. Although the mammary gland consists of a relatively simple epithelial structure with a luminal and a basal cell layers, these are indeed composed by distinct subsets of mammary epithelial cells. Flow cytometry and transplantation assay have identified several subpopulations of stem and/or progenitor cells in the mammary gland. Yet, physiological and developmental relevant information can only be obtained when investigating the stem cell hierarchy in the intact mammary gland. Genetic lineage tracing studies have offered unprecedented levels of information regarding the organization of the stem cell compartment and possible role of resident stem and/or progenitor cells at different stages of the mammary gland organogenesis. These studies, although creating a passionate debate, highlight the existence of heterogeneous stem cell compartment, where bipotent as well as unipotent mammary stem cells seems to co-exist. Genetic lineage tracing experiments provide relevant information on stem cells that are key for understanding both normal development as well as associated pathologies in human. It holds the promise of providing new insights into the cell-of-origin and heterogeneity of breast tumorigenesis.
- Mammary gland,
- mammary stem cell hierarchy,
- genetic lineage tracing,
- mouse
Citation: Liliana Osório, Fei Long, Zhongjun Zhou. Uncovering the stem cell hierarchy by genetic lineage tracing in the mammary gland[J]. AIMS Genetics, 2016, 3(2): 130-145. doi: 10.3934/genet.2016.2.130

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Abstract

The mammary gland is the distinct feature that gives the name to the class of mammals and distinguishes them from other animals. Functionally, the mammary gland is a secretory organ which main role is to produce milk to nourish the offspring. Organogenesis of the mammary gland starts during embryogenesis but occurs mainly after birth at puberty under the influence of hormonal cues. Throughout the adult life as well as during pregnancy, the mammary gland shows a remarkable regenerative ability, thus constituting an excellent model for studying stem cell biology. Although the mammary gland consists of a relatively simple epithelial structure with a luminal and a basal cell layers, these are indeed composed by distinct subsets of mammary epithelial cells. Flow cytometry and transplantation assay have identified several subpopulations of stem and/or progenitor cells in the mammary gland. Yet, physiological and developmental relevant information can only be obtained when investigating the stem cell hierarchy in the intact mammary gland. Genetic lineage tracing studies have offered unprecedented levels of information regarding the organization of the stem cell compartment and possible role of resident stem and/or progenitor cells at different stages of the mammary gland organogenesis. These studies, although creating a passionate debate, highlight the existence of heterogeneous stem cell compartment, where bipotent as well as unipotent mammary stem cells seems to co-exist. Genetic lineage tracing experiments provide relevant information on stem cells that are key for understanding both normal development as well as associated pathologies in human. It holds the promise of providing new insights into the cell-of-origin and heterogeneity of breast tumorigenesis.

References

[1]	Macias H, Hinck L (2012) Mammary gland development. Wiley Interdiscip Rev Dev Biol 1: 533-557. doi: 10.1002/wdev.35
[2]	Chepko G, Smith GH (1997) Three division-competent, structurally-distinct cell populations contribute to murine mammary epithelial renewal. Tissue Cell 29: 239-253. doi: 10.1016/S0040-8166(97)80024-9
[3]	Šale S, Lafkas D, Artavanis-Tsakonas S (2013) Notch2 genetic fate mapping reveals two previously unrecognized mammary epithelial lineages. Nat Cell Biol 15: 451-460. doi: 10.1038/ncb2725
[4]	Visvader JE, Stingl J (2014) Mammary stem cells and the differentiation hierarchy: current status and perspectives. Genes Dev 28: 1143-1158. doi: 10.1101/gad.242511.114
[5]	Deome KB, Faulkin LJ, Bern HA, Blair PB (1959) Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. Cancer Res 19: 515-520.
[6]	Smith GH (1996) Experimental mammary epithelial morphogenesis in an in vivo model: evidence for distinct cellular progenitors of the ductal and lobular phenotype. Breast Cancer Res Treat 39: 21-31. doi: 10.1007/BF01806075
[7]	Kordon EC, Smith GH (1998) An entire functional mammary gland may comprise the progeny from a single cell. Development 125: 1921-1930.
[8]	Shackleton M, Vaillant F, Simpson KJ, et al. (2006) Generation of a functional mammary gland from a single stem cell. Nature 439: 84-88. doi: 10.1038/nature04372
[9]	Stingl J, Eirew P, Ricketson I, et al. (2006) Purification and unique properties of mammary epithelial stem cells. Nature 439: 993-997.
[10]	Inman JL, Robertson C, Mott JD, et al. (2015) Mammary gland development: cell fate specification, stem cells and the microenvironment. Development 142: 1028-1042. doi: 10.1242/dev.087643
[11]	Hines WC, Su Y, Kuhn I, et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6: 779-781. doi: 10.1016/j.celrep.2014.02.021
[12]	Van Keymeulen A, Rocha AS, Ousset M, et al. (2011) Distinct stem cells contribute to mammary gland development and maintenance. Nature 479: 189-193. doi: 10.1038/nature10573
[13]	van Amerongen R, Bowman AN, Nusse R (2012) Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 11: 387-400. doi: 10.1016/j.stem.2012.05.023
[14]	Plaks V, Brenot A, Lawson DA, et al. (2013) Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep 3: 70-78. doi: 10.1016/j.celrep.2012.12.017
[15]	Prater MD, Petit V, Alasdair Russell I, et al. (2014) Mammary stem cells have myoepithelial cell properties. Nat Cell Biol 16: 942–50–1–7. doi: 10.1038/ncb3025
[16]	Kretzschmar K, Watt FM (2012) Lineage tracing. Cell 148: 33-45. doi: 10.1016/j.cell.2012.01.002
[17]	Hoess RH, Wierzbicki A, Abremski K (1986) The role of the loxP spacer region in P1 site-specific recombination. Nucleic Acids Res 14: 2287-2300.
[18]	Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21: 70-71. doi: 10.1038/5007
[19]	Zhu XD, Pan G, Luetke K, et al. (1995) Homology requirements for ligation and strand exchange by the FLP recombinase. J Biol Chem 270: 11646-11653. doi: 10.1074/jbc.270.19.11646
[20]	Metzger D, Clifford J, Chiba H, et al. (1995) Conditional site-specific recombination in mammalian cells using a ligand-dependent chimeric Cre recombinase. Proc Natl Acad Sci USA 92: 6991-6995. doi: 10.1073/pnas.92.15.6991
[21]	Feil R, Wagner J, Metzger D, et al. (1997) Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains. Biochem Biophys Res Commun 237: 752-757. doi: 10.1006/bbrc.1997.7124
[22]	Asselin-Labat M-L, Vaillant F, Sheridan JM, et al. (2010) Control of mammary stem cell function by steroid hormone signalling. Nature 465: 798-802. doi: 10.1038/nature09027
[23]	Rios AC, Fu NY, Lindeman GJ, et al. (2014) In situ identification of bipotent stem cells in the mammary gland. Nature 506: 322-327. doi: 10.1038/nature12948
[24]	Gossen M, Freundlieb S, Bender G, et al. (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268: 1766-1769. doi: 10.1126/science.7792603
[25]	Kistner A, Gossen M, Zimmermann F, et al. (1996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci USA 93: 10933-10938. doi: 10.1073/pnas.93.20.10933
[26]	Urlinger S, Baron U, Thellmann M, et al. (2000) Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc Natl Acad Sci USA 97: 7963-7968. doi: 10.1073/pnas.130192197
[27]	Mao X, Fujiwara Y, Chapdelaine A, et al. (2001) Activation of EGFP expression by Cre-mediated excision in a new ROSA26 reporter mouse strain. Blood 97: 324-326. doi: 10.1182/blood.V97.1.324
[28]	Srinivas S, Watanabe T, Lin CS, et al. (2001) Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev Biol 1: 4. doi: 10.1186/1471-213X-1-4
[29]	Madisen L, Zwingman TA, Sunkin SM, et al. (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13: 133-140. doi: 10.1038/nn.2467
[30]	Barker N, van Es JH, Kuipers J, et al. (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449: 1003-1007. doi: 10.1038/nature06196
[31]	Muzumdar MD, Tasic B, Miyamichi K, et al. (2007) A global double-fluorescent Cre reporter mouse. Genesis 45: 593-605. doi: 10.1002/dvg.20335
[32]	Livet J, Weissman TA, Kang H, et al. (2007) Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450: 56-62. doi: 10.1038/nature06293
[33]	Snippert HJ, van der Flier LG, Sato T, et al. (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143: 134-144. doi: 10.1016/j.cell.2010.09.016
[34]	Rock JR, Onaitis MW, Rawlins EL, et al. (2009) Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci USA 106: 12771-12775. doi: 10.1073/pnas.0906850106
[35]	Van Keymeulen A, Mascre G, Youseff KK, et al. (2009) Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J Cell Biol 187: 91-100. doi: 10.1083/jcb.200907080
[36]	Vasioukhin V, Degenstein L, Wise B, et al. (1999) The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci USA 96: 8551-8556. doi: 10.1073/pnas.96.15.8551
[37]	Indra AK, Warot X, Brocard J, et al. (1999) Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res 27: 4324-4327.
[38]	Nguyen H, Rendl M, Fuchs E (2006) Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127: 171-183. doi: 10.1016/j.cell.2006.07.036
[39]	Wendling O, Bornert JM, Chambon P, et al. (2009) Efficient temporally-controlled targeted mutagenesis in smooth muscle cells of the adult mouse. Genesis 47: 14-18. doi: 10.1002/dvg.20448
[40]	Wagner K-U, Boulanger CA, Henry MD, et al. (2002) An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development 129: 1377-1386.
[41]	Wang D, Cai C, Dong X, et al. (2015) Identification of multipotent mammary stem cells by protein C receptor expression. Nature 517: 81-84.
[42]	Fre S, Hannezo E, Šale S, et al. (2011) Notch lineages and activity in intestinal stem cells determined by a new set of knock-in mice. PLoS ONE 6: e25785. doi: 10.1371/journal.pone.0025785
[43]	Horvath P, Barrangou R (2010) CRISPR/Cas, the immune system of bacteria nd archaea. Science 327: 167-170. doi: 10.1126/science.1179555
[44]	Weidenheft B, Sternberg SH, Doudna JA (2012) RNA-guided genetic silencing systems in bacteria and archaea. Nature 482: 331-338. doi: 10.1038/nature10886
[45]	Cong L, Ran FA, Cox D, et al. (2013) Multiplex genome engineering using CRISPR/Cas system.Science 339: 819-823.
[46]	Wang H, Yang H, Shivalila CS, et al. (2013) One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153: 910-918. doi: 10.1016/j.cell.2013.04.025
[47]	Yang H, Wang H, Shivalila CS, et al. (2013) One-step generation of mice carrying reporter and conditional alleles by CRISPR/Cas-mediated genome engineering. Cell 154: 1370-1379. doi: 10.1016/j.cell.2013.08.022
[48]	Lafkas D, Rodilla V, Huyghe M, et al. (2013) Notch3 marks clonogenic mammary luminal progenitor cells in vivo. J Cell Biol 203: 47-56. doi: 10.1083/jcb.201307046
[49]	Lustig B, Jerchow B, Sachs M, et al. (2002) Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 22: 1184-1193. doi: 10.1128/MCB.22.4.1184-1193.2002
[50]	Zeng YA, Nusse R (2010) Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell 6: 568-577. doi: 10.1016/j.stem.2010.03.020
[51]	Zomer A, Ellenbroek SIJ, Ritsma L, et al. (2013) Intravital imaging of cancer stem cell plasticity in mammary tumors. Stem Cells 31: 602-606. doi: 10.1002/stem.1296
[52]	Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12: 954-961. doi: 10.1128/MCB.12.3.954
[53]	Van Keymeulen A, Lee MY, Ousset M, et al. (2015) Reactivation of multipotency by oncogenic PIK3CA induces breast tumour heterogeneity. Nature 525: 119-123. doi: 10.1038/nature14665

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