动物乳腺干细胞研究进展

doi:10.16431/j.cnki.1671-7236.2021.02.020

摘要/Abstract

摘要： 乳腺是一个高度活跃的器官，在青春期和生殖周期中，其上皮细胞发生了极大的变化。这些变化是由专门的干细胞和祖细胞推动的。研究乳腺干细胞对动物乳腺发育、哺乳和乳腺癌等方面都有着重大意义。如今，在乳腺干细胞生物学研究方面已经取得了显著进步。乳腺干细胞是组织学上未分化的上皮细胞，可以对称分裂产生两个相同的干细胞，或不对称地产生一个干细胞和一个腔上皮祖细胞或基底/肌上皮祖细胞。通过标记滞留细胞、染料排斥法、干细胞抗原-1标记、细胞表面标记物标记以及谱系示踪等方法可以鉴定出多种不同类型的乳腺干/祖细胞，应用多种不同方法分离鉴定乳腺干细胞有助于深入了解其异质性。乳腺的研究主要分为6个阶段：胚胎期、青春期、性成熟期、妊娠期、泌乳期和退化期。在乳腺不同发育阶段，乳腺干/祖细胞的类型及特性不同。有研究表明，在胚胎期就有基底和管腔谱系的祖细胞产生，静止的乳腺干细胞也可能来自于胚胎期，出生后，静止干细胞可以在卵巢激素的刺激作用下重新进入细胞周期，产生乳腺细胞谱系和自我更新。作者介绍了乳腺干细胞和祖细胞的存在、形态特征、鉴定方法，简述了乳腺干细胞在胚胎期、青春期和妊娠期的特征，分析了目前该领域研究的不足之处以及对未来应用的展望。

关键词: 乳腺发育; 乳腺干细胞; 鉴定; 细胞表面标记; 谱系示踪

Abstract: The mammary gland is a highly active organ whose epithelium changes dramatically during puberty and reproductive cycles.These changes are driven by specialized stem and progenitor cells.The research of mammary stem cells is of great significance to animal mammary gland development,lactation and breast cancer.Today,significant advances have been made in the biology of mammary stem cells.Mammary stem cells are histologically undifferentiated epithelial cells that can divide symmetrically to produce two identical stem cells,or asymmetrically to produce one kind of stem cell and one kind of luminal epithelial progenitor cell or basal/myoepithelial progenitor cell.A variety of different types of mammary stem/progenitor cells can be identified by labeling retained cells,dye exclusion,stem cell antigen-1 labeling,cell surface marker labeling,and lineage tracing.The isolation and identification of mammary stem cells by different methods is helpful to understand the heterogeneity.Mammary research is divided into six stages:Embryo,adolescence,sexual maturity,pregnancy,lactation and involuted phases.The types and characteristics of mammary gland stem/progenitor cells are different in different stages of mammary gland development.Studies have shown that the progenitor cells with basal and luminal lineages are produced in embryo phase.Quiescent mammary stem cells may also come from the embryo stage.After birth,quiescent mammary stem cells can be stimulated by ovarian hormones to re-enter the cell cycle,producing a mammary cell lineage and self-renewal.This paper introduced the existence,morphological characteristics and identification methods of mammary stem cells and progenitor cells,briefly described the characteristics of mammary stem cells in embryonic,adolescent and pregnancy,analyzed the current shortcomings and prospects for future application,in order to further study animal breast stem cells.

Key words: mammary gland development; mammary stem cell; identification; cell surface marker; lineage tracer

中图分类号:

S852.2

王小月, 苗家麟, 董旭晟, 王中华, 林雪彦, 王云, 侯秋玲. 动物乳腺干细胞研究进展[J]. 中国畜牧兽医, 2021, 48(2): 581-591.

WANG Xiaoyue, MIAO Jialin, DONG Xusheng, WANG Zhonghua, LIN Xueyan, WANG Yun, HOU Qiuling. Advances in Animal Mammary Stem Cell Research[J]. China Animal Husbandry and Veterinary Medicine, 2021, 48(2): 581-591.

参考文献

[1] HENNIGHAUSEN L,ROBINSON G W.Information networks in the mammary gland[J].Nature Reviews Molecular Cell Biology,2005,6(9):715-725.
[2] FU N,NOLAN E,LINDEMAN G J,et al.Stem cells and the differentiation hierarchy in mammary gland development[J].Physiological Reviews,2020,100(2):489-523.
[3] DEOME K B,FAULKIN L J,BERN H A,et al.Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice[J].Cancer Research,1959,19(5):515-520.
[4] HOSHINO K,GARDNER W U.Transplantability and life span of mammary gland during serial transplantation in mice[J].Nature,1967,213(5072):193-194.
[5] DANIEL C W,DEOME K B,YOUNG J T,et al.The in vivo life span of normal and preneoplastic mouse mammary glands:A serial transplantation study[J].Proceedings of the National Academy of Sciences of the United States of America,1968,61(1):53-60.
[6] SMITH G H,MEDINA D.A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland[J].Journal of Cell Science,1988,90(Pt 1):173-183.
[7] FU N,RIOS A C,PAL B,et al.Identification of quiescent and spatially restricted mammary stem cells that are hormone responsive[J].Nature Cell Biollogy,2017,19(3):164-176.
[8] CAI S,KALISKY T,SAHOO D,et al.A quiescent bcl11b high stem cell population is required for maintenance of the mammary gland[J].Cell Stem Cell,2017,20(2):247-260.
[9] RIOS A C,FU N Y,LINDEMAN G J,et al.In situ identification of bipotent stem cells in the mammary gland[J].Nature,2014,506(7488):322-327.
[10] WANG D,CAI C,DONG X,et al.Identification of multipotent mammary stem cells by protein C receptor expression[J].Nature,2015,517(7532):81-84.
[11] SPIKE B T,KELBER J A,BOOKER E,et al.CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo[J].Stem Cell Reports,2014,2(4):427-439.
[12] NGUYEN L V,MAKAREM M,CARLES A,et al.Clonal analysis via barcoding reveals diverse growth and differentiation of transplanted mouse and human mammary stem cells[J].Cell Stem Cell,2014,14(2):253-263.
[13] VAN KEYMEULEN A,ROCHA A S,OUSSET M,et al.Distinct stem cells contribute to mammary gland development and maintenance[J].Nature,2011,479(7372):189-193.
[14] WUIDART A,SIFRIM A,FIORAMONTI M,et al.Early lineage segregation of multipotent embryonic mammary gland progenitors[J].Nature Cell Biollogy,2018,20(6):666-676.
[15] LILJA A M,RODILLA V,HUYGHE M,et al.Clonal analysis of notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland[J].Nature Cell Biollogy,2018,20(6):677-687.
[16] DONATI G,WATT F M.Stem cell heterogeneity and plasticity in epithelia[J].Cell Stem Cell,2015,16(5):465-476.
[17] INGTHORSSON S,BRIEM E,BERGTHORSSON J T,et al.Epithelial plasticity during human breast morphogenesis and cancer progression[J].Journal of Mammary Gland Biology and Neoplasia,2016,21(3-4):139-148.
[18] CHAKRABARTI R,CELI-TERRASSA T,KUMAR S,et al.Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche[J].Science,2018,360(6396):eaan4153.
[19] CORSA A S,MACDOUGALD O A.Cyclical dedifferentiation and redifferentiation of mammary adipocytes[J].Cell Metabolism,2018,28(2):187-189.
[20] WANG Q A,SONG A,CHEN W,et al.Reversible de-differentiation of mature white adipocytes into preadipocyte-like precursors during lactation[J].Cell Metabolism,2018,28(2):282-288.
[21] FRANK-KAMENETSKII A,BOOTH B W.Redirec-ting normal and cancer stem cells to a mammary epithelial cell fate[J].Journal of Mammary Gland Biology and Neoplasia,2019,24(4):285-292.
[22] SCHEELE C L,HANNEZO E,MURARO M J,et al.Identity and dynamics of mammary stem cells during branching morphogenesis[J].Nature,2017,542(7641):313-317.
[23] HOVEY R C,TROTT J F,VONDERHAAR B K.Establishing a framework for the functional mammary gland:From endocrinology to morphology[J].Journal of Mammary Gland Biology and Neoplasia,2002,7(1):17-38.
[24] HENS J R,WYSOLMERSKI J J.Key stages of mammary gland development:Molecular mechanisms involved in the formation of the embryonic mammary gland[J].Breast Cancer Research,2005,7(5):220-224.
[25] LU P,STERNLICHT M D,WERB Z.Comparative mechanisms of branching morphogenesis in diverse systems[J].Journal of Mammary Gland Biology and Neoplasia,2006,11(3-4):213-228.
[26] VELTMAAT J M,MAILLEUX A A,THIERY J P,et al.Mouse embryonic mammogenesis as a model for the molecular regulation of pattern formation[J].Differentiation,2003,71(1):1-17.
[27] ROBINSON G W.Cooperation of signalling pathways in embryonic mammary gland development[J].Nature Reviews Genetics,2007,8(12):963-972.
[28] WATSON C J,KHALED W T.Mammary development in the embryo and adult:A journey of morphogenesis and commitment[J].Development,2008,135(6):995-1003.
[29] LU P,EWALD A J,MARTIN G R,et al.Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis[J].Developmental Biology,2008,321(1):77-87.
[30] INMAN J L,ROBERTSON C,MOTT J D,et al.Mammary gland development:Cell fate specification,stem cells and the microenvironment[J].Development,2015,142(6):1028-1042.
[31] VISVADER J E,STINGL J.Mammary stem cells and the differentiation hierarchy:Current status and perspectives[J].Genes & Development,2014,28(11):1143-1158.
[32] ZHOU J,CHEN Q,ZOU Y,et al.Stem cells and cellular origins of mammary gland:Updates in rationale,controversies,and cancer relevance[J].Stem Cells International,2019,2019:4247168.
[33] KREUZALER P A,STANISZEWSKA A D,LI W,et al.Stat3 controls lysosomal-mediated cell death in vivo[J].Nature Cell Biology,2011,13(3):303-309.
[34] SARGEANT T J,LLOYD-LEWIS B,RESEMANN H K,et al.Stat3 controls cell death during mammary gland involution by regulating uptake of milk fat globules and lysosomal membrane permeabilization[J].Nature Cell Biology,2014,16(11):1057-1068.
[35] CAPUCO A V,WOOD D L,BALDWIN R,et al.Mammary cell number,proliferation,and apoptosis during a bovine lactation:Relation to milk production and effect of bST[J].Journal of Dairy Science,2001,84(10):2177-2187.
[36] CROSSMAN J,ELYASI M,EL-BIALY T,et al.Cementum regeneration using stem cells in the dog model:A systematic review[J].Archives of Oral Biology,2018,91:78-90.
[37] MACIAS H,HINCK L.Mammary gland development[J].Wiley Interdisciplinary Reviews Developmental Biology,2012,1(4):533-557.
[38] CHEPKO G,SMITH G H.Mammary epithelial stem cells:Our current understanding[J].Journal of Mammary Gland Biology and Neoplasia,1999,4(1):35-52.
[39] CHEPKO G,SMITH G H.Three division-competent,structurally distinct cell populations contribute to murine mammary epithelial renewal[J].Tissue Cell,1997,29(2):239-253.
[40] WELM B E,TEPERA S B,VENEZIA T,et al.Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population[J].Developmental Biology,2002,245(1):42-56.
[41] ZEPS N,BENTEL J M,PAPADIMITRIOU J M,et al.Estrogen receptor-negative epithelial cells in mouse mammary gland development and growth[J].Differentiation,1998,62(5):221-226.
[42] SMITH G H.Label-retaining epithelial cells in mouse mammary gland divide asymmetrically and retain their template DNA strands[J].Devlopment,2005,132(4):681-687.
[43] CAPUCO A V,CHOUDHARY R K.Symposium review:Determinants of milk production:Under-standing population dynamics in the bovine mammary epithelium[J].Journal of Dairy Science,2020,103(3):2928-2940.
[44] BUSSARD K M,BOULANGER C A,KITTRELL F S,et al.Immortalized,premalignant epithelial cell populations contain long-lived,label-retaining cells that asymmetrically divide and retain their template DNA[J].Breast Cancer Research,2010,12(5):R86.
[45] BORAS-GRANIC K,DANN P,WYSOLMERSKI J J.Embryonic cells contribute directly to the quiescent stem cell population in the adult mouse mammary gland[J].Breast Cancer Research,2014,16(6):487.
[46] RAGLE L E,BRUNO R D,BOULANGER C A,et al.Long-label-retaining mammary epithelial cells are created early in ductal development and distributed throughout the branching ducts[J].Mechanisms of Ageing and Development,2019,159:103565.
[47] ZHOU S,SCHUETZ J D,BUNTING K D,et al.The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype[J].Nature Medicine,2001,7(9):1028-1034.
[48] BUNTING K D.ABC transporters as phenotypic markers and functional regulators of stem cells[J].Stem Cells,2002,20(1):1120.
[49] ALVI A J,CLAYTON H,JOSHI C,et al.Functional and molecular characterisation of mammary side population cells[J].Breast Cancer Research,2003,5(1):R1-R8.
[50] SHACKLETON M,VAILLANT F,SIMPSON K J,et al.Generation of a functional mammary gland from a single stem cell[J].Nature,2006,439(7072):84-88.
[51] STINGL J,EAVES C J,WATSON C J.Phenotypic characterization of mouse mammary epithelial stem and progenitor cells[J].Breast Cancer Research,2006,8:S1-S20.
[52] LAURENCE F,ERIC C,FREDERIC D.Molecular signature of the putative stem/progenitor cells committed to the development of the bovine mammary gland at puberty[J].Scientific Reports,2018,8(1):16194.
[53] RAUNER G,LEDET M M,VAN DE WALLE G R.Conserved and variable:Understanding mammary stem cells across species[J].Cytometry Part A,2018,93(1):125-136.
[54] DOS SANTOS C O,REBBECK C,ROZHKOVA E,et al.Molecular hierarchy of mammary differentiation yields refined markers of mammary stem cells[J].Proceedings of the National Academy of Sciences of the United States of America,2013,110(18):7123-7130.
[55] STINGL J,EIREW P,RICKETSON I,et al.Purification and unique properties of mammary epithelial stem cells[J].Nature,2006,439(7079):993-997.
[56] ASSELIN-LABAT M L,SHACKLETON M,STINGL J,et al.Steroid hormonereceptor status of mouse mammary stem cells[J].Journal of the National Cancer Institute,2006,98(14):1011-1014.
[57] SHEHATA M,TESCHENDORFF A,SHARP G,et al.Phenotypicand functional characterization of the luminal cell hierarchy of themammary gland[J].Breast Cancer Research,2012,14(5):R134.
[58] FU N,LINDEMAN G J,VISVADER J E.The mammary stem cell hierarchy[J].Current Topics in Developmental Biology,2014,107:133-160.
[59] EIREW P,STINGL J,RAOUF A,et al.A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability[J].Nature Medicine,2008,14(12):1384-1389.
[60] LIM E,VAILLANT F,WU D,et al.Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers[J].Nature Medicine,2009,15(8):907-913.
[61] STINGL J,EIREW P,RICKETSON I,et al.Purification and unique properties of mammaryepi-thelial stem cells[J].Nature,2006,439(7079):993-997.
[62] MAKAREM M,KANNAN N,NGUYEN L V,et al.Developmental changes in the in vitro activated regenerative activity of primitive mammary epithelial cells[J].PLoS Biology,2013,11(8):e1001630.
[63] PRATER M D,PETIT V,ALASDAIR RUSSELL I,et al.Mammary stem cells have myoepithelial cell properties[J].Nature Cell Biology,2014,16(10):942-950.
[64] CODEGA P,SILVA-VARGAS V,PAUL A,et al.Prospective identification and purification of quiescent adult neural stem cells from their in vivo niche[J].Neuron,2014,82(3):545-559.
[65] FOUDI A,HOCHEDLINGER K,BUREN D V,et al.Hock analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cells[J].Nature Biotechnology,2009,27(1):84-90.
[66] WILSON A E,LAURENTI G,OSER R C,et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair[J].Cell,2008,135(6):1118-1129.
[67] PECE S,TOSONI D,CONFALONIERI S,et al.Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content[J].Cell,2010,140(1):62-73.
[68] FINOT L,CHANAT E,DESSAUGE F.Mammary epithelial cell lineage changes during cow's life[J].Journal of Mammary Gland Biology and Neoplasia,2019,24(2):185-197.
[69] SCHEPERS A G,SNIPPERT H J,STANGE D E,et al.Lineage tracing reveals Lgr5⁺ stem cell activity in mouse intestinal adenomas[J].Science,2012,337(6095):730-735.
[70] ROHRSCHNEIDER L R,CUSTODIO J M,ANDERSON T A,et al.The intron 5/6 promoter region of the ship1 gene regulates expression in stem/progenitor cells of the mouse embryo[J].Developmental Biology,2005,283(2):503-521.
[71] BAI L,ROHRSCHNEIDER L R.s-SHIP promoter expression marks activated stem cells in developing mouse mammary tissue[J].Genes & Development,2010,24(17):1882-1892.
[72] LUSTIG B,JERCHOW B,SACHS M,et al.Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors[J].Molecular and Cellular Biology,2002,22(4):1184-1193.
[73] OLABI S,UCAR A,BRENNAN K,et al.Integrin-Rac signalling for mammary epithelial stem cell self-renewal[J].Breast Cancer Research,2018,20(1):128.
[74] ZENG Y A,NUSSE R.Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture[J].Cell Stem Cell,2010,6(6):568-577.
[75] VAN AMERONGEN R,BOWMAN A N,NUSSE R.Developmental stage and time dictate the fate of Wnt/β-Catenin-responsive stem cells in the mammary gland[J].Cell Stem Cell,2012,11(3):387-400.
[76] BLANPAIN C,FUCHS E.Plasticity of epithelial stem cells in tissue regeneration[J].Science,2014,344(6189):1242281.
[77] RODILLA V,DASTI A,HUYGHE M,et al.Luminal progenitors restrict their lineage potential during mammary gland development[J].PLoS Biology,2015,13(20):e1002069.
[78] SCHEELE C L,HANNEZO E,MURARO M J,et al.Identity and dynamics of mammary stem cells during branching morphogenesis[J].Nature,2017,542(7641):313-317.
[79] DAVIS F M,LLOYD-LEWIS B,HARRIS O B,et al.Single-cell lineage tracing in the mammary gland reveals stochastic clonal dispersion of stem/progenitor cell progeny[J].Nature Communications,2016,7:13053.
[80] BLAAS L,PUCCI F,MESSAL H A,et al.Lgr6 labels a rare population of mammary gland progenitor cells that are able to originate luminal mammary tumours[J].Nature Cell Biology,2016,18(12):1346-1356.
[81] VAN KEYMEULEN A,FIORAMONTI M,CENTONZE A,et al.Lineage-restricted mammary stem cells susta in the development,homeostasis,and regeneration of the estrogen receptor positive lineage[J].Cell Reports,2017,20(7):1525-1532.
[82] SMITH G H,MEDINA D.Does the mouse mammary gland arise from unipotent or multipotent mammary stem/progenitor cells?[J].Journal of Mammary Gland Biology and Neoplasia,2018,23(1-2):1-3.
[83] LEE E,PIRANLIOGLU R,WICHA M S,et al.Plasticity and potency of mammary stem cell subsets during mammary gland development[J].International Journal of Molecular Sciences,2019,20(9):2357.
[84] SPIKE BT,ENGLE D D,LIN J C,et al.A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer[J].Cell Stem Cell,2012,10(2):183-197.
[85] WANSBURY O,MACKAY A,KOGATA N,et al.Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment[J].Breast Cancer Research,2011,13(4):R79.
[86] LLOYD-LEWIS B,DAVIS F M,HARRIS O B,et al.Neutral lineage tracing of proliferative embryonic and adult mammary stem/progenitor cells[J].Development,2018,145(14):dev164079.
[87] CHEPKO G,DICKSON R B.Ultrastructure of the putative stem cell niche in rat mammary epithelium[J].Tissue Cell,2003,35(2):83-93.
[88] PAINE G,CHAUVIERE A,LANDUA J,et al.A geometrically-constrained mathematical model of mammary gland ductal elongation reveals novel cellular dynamics within the terminal end bud[J].PLoS Computational Biology,2016,12(4):e1004839.
[89] SREEKUMAR A,ROARTY K,ROSEN J M,et al.The mammary stem cell hierarchy:A looking glass into heterogeneous breast cancer landscapes[J].Endocrine-related Cancer,2015,22(6):T161-T176.
[90] WILLIAMS I M,DANIEL C W.Mammary ductal elongation:Differentiation of myoepithelium and basal lamina during branching morphogenesis[J].Developmental Biology,1983,97(2):274-290.
[91] SRINIVASAN K,STRICKLAND P,VALDES A,et al.Netrin-1/neogenin interaction stabilizes multipotent progenitor cap cells during mammary gland morpho-genesis[J].Developmental Biology,2003,4(3):371-382.
[92] BRISKEN C,MALLEY B O.Hormone action in the mammary gland[J].Cold Spring Harbor Perspectives in Biology,2010,2(12):a003178.
[93] SREEKUMAR A,TONEFF M J,TOH E,et al.WNT-mediated regulation of FOXO1 constitutes a critical axis maintaining pubertal mammary stem cell homeostasis[J].Developmental Cell,2017,43(4):436-448.
[94] FU N,PAL B,CHEN Y,et al.Foxp1 is indispensable for ductal morphogenesis and controls the exit of mammary stem cells from quiescence[J].Develop-mental Cell,2018,47(5):629-644.
[95] SONG W,WANG R,JIANG W,et al.Hormones induce the formation of luminal-derived basal cells in the mammary gland[J].Cell Research,2019,29(3):206-220.
[96] FINOT L,CHANAT E,DESSAUGE F.Molecular signature of the putative stem/progenitor cells committed to the development of the bovine mammary gland at puberty[J].Scientific Reports,2018,8:16194.