{"paper_id":"af5a6fc8-aa44-4fea-a681-06f1b359fd0b","body_text":"Abstract\nThe human endometrium (lining of the uterus) is a dynamic remodeling tissue undergoing more than 400 cycles of regeneration, differentiation, and shedding during a woman’s reproductive years. Endometrial regeneration also follows childbirth, almost complete resection and in postmenopausal women taking estrogen replacement therapy. In nonmenstruating species (e.g. rodents) there are cycles of endometrial growth and apoptosis, rather than physical shedding. The endometrium comprises epithelial-lined glands extending from the surface epithelium to the myometrium supported by extensive stroma. Remodeling of the endometrium is regulated by the co-ordinated and sequential actions of estrogen and progesterone in preparation for blastocyst implantation on a monthly basis in women and every 4–5 days in mice. Adult stem/progenitor cells are likely responsible for endometrial regeneration. Since there are no specific stem cell markers, initial studies using functional approaches identified candidate epithelial and stromal endometrial stem/progenitor cells as colony-forming cells/units (CFU) and side population (SP) cells. Recently, a subpopulation of human endometrial stromal cells with mesenchymal stem cell–like properties of CFU activity and multilineage differentiation have been isolated by their co-expression of CD146 and PDGF-receptor \\(\\beta\\). Candidate epithelial and stromal stem/progenitor cells have also been identified in mouse endometrium as rare label-retaining cells (LRC) in the luminal epithelium and as perivascular cells at the endometrial myometrial junction, respectively. While epithelial and most stromal LRC do not express estrogen receptor α (ERα), they rapidly proliferate on estrogen stimulation, most likely mediated by neighboring ERα-expressing niche cells. It is likely that these newly identified endometrial stem/progenitor cells may play key roles in the development of gynecological diseases associated with abnormal endometrial proliferation such as endometriosis and endometrial cancer. The endometrium may also provide a readily available source of mesenchymal stem-like cells for tissue engineering purposes with possible applications not only to urogynecology but also to heart disease, and soft tissue and bone repair.\nSimilar content being viewed by others\nReferences\nGargett CE. Uterine stem cells: What is the evidence? Hum Reprod Update. 2007;13:87–101.\nJabbour HN, Kelly RW, Fraser HM, Critchley HO. Endocrine regulation of menstruation. Endocr Rev. 2006;27:17–46.\nMcLennan CE, Rydell AH. Extent of endometrial shedding during normal menstruation. Obstet Gynecol. 1965;26:605–21.\nGargett CE. Identification and characterisation of human endometrial stem/progenitor cells. Aust N Z J Obstet Gynaecol. 2006;46:250–3.\nGargett CE, Chan RW, Schwab KE. Endometrial stem cells. Curr Opin Obstet Gynecol. 2007;19:377–83.\nGargett C, Chan R, Schwab K. Hormone and growth factor signaling in endometrial renewal: role of stem/progenitor cells. Mol Cell Endocrinol. 2008;288:22–9.\nUduwela AS, Perera MA, Aiqing L, Fraser IS. Endometrial-myometrial interface: relationship to adenomyosis and changes in pregnancy. Obstet Gynecol Surv. 2000;55:390–400.\nNoe M, Kunz G, Herbertz M, Mall G, Leyendecker G. The cyclic pattern of the immunocytochemical expression of oestrogen and progesterone receptors in human myometrial and endometrial layers: characterization of the endometrial-subendometrial unit. Hum Reprod. 1999;14:190–7.\nOkulicz WC, Ace CI, Scarrell R. Zonal changes in proliferation in the rhesus endometrium during the late secretory phase and menses. Proc Soc Exp Biol Med. 1997;214:132–8.\nPadykula HA. Regeneration in the primate uterus: the role of stem cells. Ann N Y Acad Sci. 1991;622:47–56.\nSpencer TE, Hayashi K, Hu J, Carpenter KD. Comparative developmental biology of the mammalian uterus. Curr Top Dev Biol. 2005;68:85–122.\nConneely OM, Mulac-Jericevic B, Lydon JP, De Mayo FJ. Reproductive functions of the progesterone receptor isoforms: lessons from knock-out mice. Mol Cell Endocrinol. 2001;179:97–103.\nSlayden OD, Brenner RM. Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists. Arch Histol Cytol. 2004;67:393–409.\nBrenner RM, Slayden OD, Rodgers WH, Critchley HO, Carroll R, Nie XJ, et al. Immunocytochemical assessment of mitotic activity with an antibody to phosphorylated histone H3 in the macaque and human endometrium. Hum Reprod. 2003;18:1185–93.\nFerenczy A, Bertrand G, Gelfand MM. Proliferation kinetics of human endometrium during the normal menstrual cycle. Am J Obstet Gynecol. 1979;133:859–67.\nPadykula HA, Coles LG, Okulicz WC, Rapaport SI, McCracken JA, King NW, Jr., et al. The basalis of the primate endometrium: a bifunctional germinal compartment. Biol Reprod. 1989;40: 681–90.\nGargett CE. Stem cells in gynaecology. Aust N Z J Obstet Gynaecol. 2004;44:380–6.\nLudwig H, Metzger H, Frauli M. Endometrium: tissue remodelling and regeneration. In: D’Arcangues C, Fraser IS, Newton JR, Odlind V, editors. Contraception and mechanisms of endometrial bleeding. Melbourne: Cambridge University Press; 1990. pp. 441–66.\nOkulicz WC, Scarrell R. Estrogen receptor alpha and progesterone receptor in the rhesus endometrium during the late secretory phase and menses. Proc Soc Exp Biol Med. 1998;218: 316–21.\nKaitu’u-Lino TJ, Morison NB, Salamonsen LA. Estrogen is not essential for full endometrial restoration after breakdown: lessons from a mouse model. Endocrinology. 2007;148:5105–11.\nPonnampalam AP, Weston GC, Trajstman AC, Susil B, Rogers PA. Molecular classification of human endometrial cycle stages by transcriptional profiling. Mol Hum Reprod. 2004;10: 879–93.\nTalbi S, Hamilton AE, Vo KC, Tulac S, Overgaard MT, Dosiou C, et al. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2006;147:1097–121.\nSalamonsen LA. Tissue injury and repair in the female human reproductive tract. Reproduction. 2003;125:301–11.\nFeeley KM, Wells M. Hormone replacement therapy and the endometrium. J Clin Pathol. 2001;54:435–40.\nHu J, Gray CA, Spencer TE. Gene expression profiling of neonatal mouse uterine development. Biol Reprod. 2004;70:1870–6.\nWalmer DK, Wrona MA, Hughes CL, Nelson KG. Lactoferrin expression in the mouse reproductive tract during the natural estrous cycle: correlation with circulating estradiol and progesterone. Endocrinology. 1992;131:1458–66.\nWood GA, Fata JE, Watson KL, Khokha R. Circulating hormones and estrous stage predict cellular and stromal remodeling in murine uterus. Reproduction. 2007;133:1035–44.\nFinn CA, Martin L. The cellular response of the uterus of the aged mouse to oestrogen and progesterone. J Reprod Fertil. 1969;20:545–7.\nAllen E. The oestrous cycle in the mouse. Am J Anat. 1922;30:297–371.\nCouse JF, Korach KS. Estrogen receptor null mice: what have we learned and where will they lead us? Endocr Rev. 1999;20: 358–417.\nLydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA, Jret al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9: 2266–78.\nKurita T, Young P, Brody JR, Lydon JP, O’Malley BW, Cunha GR. Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis. Endocrinology. 1998;139: 4708–4713.\nCouse JF, Curtis SW, Washburn TF, Lindzey J, Golding TS, Lubahn DB, et al. Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol. 1995;9:1441–54.\nCooke PS, Buchanan DL, Young P, Setiawan T, Brody J, Korach KS, et al. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci U S A. 1997;94:6535–40.\nKurita T, Medina R, Schabel AB, Young P, Gama P, Parekh TV, et al. The activation function-1 domain of estrogen receptor alpha in uterine stromal cells is required for mouse but not human uterine epithelial response to estrogen. Differentiation. 2005;73:313–22.\nNelson KG, Takahashi T, Bossert NL, Walmer DK, McLachlan JA. Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci U S A. 1991;88:21–5.\nSato T, Wang G, Hardy MP, Kurita T, Cunha GR, Cooke PS. Role of systemic and local IGF-I in the effects of estrogen on growth and epithelial proliferation of mouse uterus. Endocrinology. 2002;143:2673–9.\nMartin L, Finn CA. Interactions of oestradiol and progestins in the mouse uterus. J Endocrinol. 1970;48:109–15.\nMartin L, Finn CA, Trinder G. Hypertrophy and hyperplasia in the mouse uterus after oestrogen treatment: an autoradiographic study. J Endocrinol. 1973;56:133–144.\nChan RW, Gargett CE. Identification of label-retaining cells in mouse endometrium. Stem Cells. 2006;24:1529–1538.\nMartin L, Finn CA, Trinder G. Hypertrophy and hyperplasia in the mouse uterus after oestrogen treatment: an autoradiographic study. J Endocrinol. 1973;56:133–144.\nBrody JR, Cunha GR. Histologic, morphometric, and immunocytochemical analysis of myometrial development in rats and mice: I. Normal development. Am J Anat. 1989;186:1–20.\nPrianishnikov VA. On the concept of stem cell and a model of functional-morphological structure of the endometrium. Contraception 1978;18:213–223.\nChan RW, Schwab KE, Gargett CE. Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod. 2004;70:1738–50.\nGargett CE. Endometrial stem cells. In: Aplin JR, Fazleabas AT, Glasser SR, Giudice LC, editors. The endometrium: molecular, cellular and clinical perspectives. 2nd ed. London: Taylor and Francis Medical Publishing; 2007. pp. 135–153.\nSchwab KE, Chan RW, Gargett CE. Putative stem cell activity of human endometrial epithelial and stromal cells during the menstrual cycle. Fertil Steril. 2005;84 Suppl 2:1124–30.\nKato K, Yoshimoto M, Kato K, Adachi S, Yamayoshi A, Arima T, et al. Characterization of side-population cells in human normal endometrium. Hum Reprod. 2007;22:1214–23.\nSmalley MJ, Clarke RB. The mammary gland “side population”: a putative stem/progenitor cell marker? J Mammary Gland Biol Neoplasia. 2005;10:37–47.\nGargett CE, Zillwood R, Schwab KE. Characterising the stem cell activity of human endometrial cells. Hum Reprod. 2005;20(Suppl 1):i95.\nCervello I, Martinez-Conejero JA, Horcajadas JA, Pellicer A, Simon C. Identification, characterization and co-localization of label-retaining cell population in mouse endometrium with typical undifferentiated markers. Hum Reprod. 2007;22:45–51.\nSzotek PP, Chang HL, Zhang L, Preffer F, Dombkowski D, Donahoe PK, et al. Adult mouse myometrial label-retaining cells divide in response to gonadotropin stimulation. Stem Cells. 2007;25:1317–25.\nGargett CE, Chan RWS. Role of stem cells in estrogen induced endometrial regeneration. Reprod Sci. 2007;14(1 Suppl): 214A.\nSchwab KE, Gargett CE. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum Reprod. 2007;22:2903–11.\nShi S, Gronthos S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res. 2003;18:696–704.\nZuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell. 2002;13:4279–95.\nGronthos S, Brahim J, Li W, Fisher LW, Cherman N, Boyde A, et al. Stem cell properties of human dental pulp stem cells. J Dent Res. 2002;81:531–5.\nWolff EF, Wolff AB, Hongling D, Taylor HS. Demonstration of multipotent stem cells in the adult human endometrium by in vitro chondrogenesis. Reprod Sci. 2007;14:524–33.\nBiervliet FP, Maguiness SD, Robinson J, Killick SR. A successful cycle of IVF-ET after treatment of endometrial ossification; case report and review. J Obstet Gynaecol. 2004;24:472–3.\nvan Os R, Kamminga LM, de Haan G. Stem cell assays: something old, something new, something borrowed. Stem Cells. 2004;22:1181–90.\nBird CC, Willis RA. The production of smooth muscle by the endometrial stroma of the adult human uterus. J Path Bact. 1965;90:75–81.\nRoth E, Taylor HB. Heterotopic cartilage in the uterus. Obstet Gynecol. 1966;27:838–44.\nMazur MT, Kraus FT. Histogenesis of morphologic variations in tumors of the uterine wall. Am J Surg Pathol. 1980;4:59–74.\nOno M, Maruyama T, Masuda H, Kajitani T, Nagashima T, Arase T, et al. Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proc Natl Acad Sci U S A. 2007;104:18700–5.\nKiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109–21.\nPalmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 2000;425:479–94.\nSnyder EY, Loring JF. A role for stem cell biology in the physiological and pathological aspects of aging. J Am Geriatr Soc. 2005;53:S287–91.\nKobayashi A, Behringer RR. Developmental genetics of the female reproductive tract in mammals. Nat Rev Genet. 2003;4: 969–80.\nMasuda H, Maruyama T, Hiratsu E, Yamane J, Iwanami A, Nagashima T, et al. Noninvasive and real-time assessment of reconstructed functional human endometrium in NOD/SCID/gamma c(null) immunodeficient mice. Proc Natl Acad Sci U S A. 2007;104:1925–30.\nBlau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? Cell. 2001;105:829–41.\nRaff M. Adult stem cell plasticity: fact or artifact? Annu Rev Cell Dev Biol. 2003;19:1–22.\nKorbling M, Estrov Z. Adult stem cells for tissue repair – a new therapeutic concept? N Engl J Med. 2003;349:570–582.\nWagers AJ, Weissman IL. Plasticity of adult stem cells. Cell. 2004;116:639–48.\nKinnaird T, Stabile E, Burnett MS, Shou M, Lee CW, Barr S, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation. 2004;109:1543–9.\nPauwelyn KA, Verfaillie CM. Transplantation of undifferentiated, bone marrow-derived stem cells. Curr Top Dev Biol. 2006;74:201–51.\nBratincsak A, Brownstein MJ, Cassiani-Ingoni R, Pastorino S, Szalayova I, Toth ZE, et al. CD45-positive blood cells give rise to uterine epithelial cells in mice. Stem Cells. 2007;25:2820–6.\nDu H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25:2082–6.\nTaylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292:81–5.\nKim JY, Tavare S, Shibata D. Counting human somatic cell replications: methylation mirrors endometrial stem cell divisions. Proc Natl Acad Sci U S A. 2005;102:17739–44.\nTanaka M, Kyo S, Kanaya T, Yatabe N, Nakamura M, Maida Y, et al. Evidence of the monoclonal composition of human endometrial epithelial glands and mosaic pattern of clonal distribution in luminal epithelium. Am J Pathol. 2003;163:295–301.\nSalamonsen LA, Lathbury LJ. Endometrial leukocytes and menstruation. Hum Reprod Update. 2000;6:16–27.\nCui CH, Uyama T, Miyado K, Terai M, Kyo S, Kiyono T, et al. Menstrual blood-derived cells confer human dystrophin expression in the murine model of Duchenne muscular dystrophy via cell fusion and myogenic transdifferentiation. Mol Biol Cell. 2007;18:1586–94.\nGargett CE, Chan RW. Endometrial stem/progenitor cells and proliferative disorders of the endometrium. Minerva Ginecol. 2006;58:511–26.\nGiudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789–99.\nLeyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod. 2002;17:2725–36.\nStarzinski-Powitz A, Zeitvogel A, Schreiner A, Baumann R. In search of pathogenic mechanisms in endometriosis: the challenge for molecular cell biology. Curr Mol Med. 2001;1:655–64.\nTanaka T, Nakajima S, Umesaki N. Cellular heterogeneity in long-term surviving cells isolated from eutopic endometrial, ovarian endometrioma and adenomyosis tissues. Oncol Rep. 2003;10:1155–60.\nJimbo H, Hitomi Y, Yoshikawa H, Yano T, Momoeda M, Sakamoto A, et al. Evidence for monoclonal expansion of epithelial cells in ovarian endometrial cysts. Am J Pathol. 1997;150:1173–8.\nWu Y, Basir Z, Kajdacsy-Balla A, Strawn E, Macias V, Montgomery K, et al. Resolution of clonal origins for endometriotic lesions using laser capture microdissection and the human androgen receptor (HUMARA) assay. Fertil Steril. 2003;79 Suppl 1:710–7.\nMiller SJ, Lavker RM, Sun TT. Interpreting epithelial cancer biology in the context of stem cells: tumor properties and therapeutic implications. Biochim Biophys Acta. 2005;1756:25–52.\nPardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3:895–902.\nPolyak K, Hahn WC. Roots and stems: stem cells in cancer. Nat Med. 2006;12:296–300.\nDalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med. 2007;58:267–284.\nLapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8\nAl-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.\nO’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10.\nDalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007;104:10158–63.\nRicci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5.\n98. Hubbard S, Chan RWS, Gargett CE. Preliminary evidence for progenitor/stem cells in human endometrial adenocarcinoma. In: 5th International Society for Stem Cell Research Annual Meeting; 2007 17–20 June; Cairns, Australia; 2007. p. 85.\nAmant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet. 2005;366:491–505.\nRahaman MN, Mao JJ. Stem cell-based composite tissue constructs for regenerative medicine. Biotechnol Bioeng. 2005;91:261–84.\nDeLancey JO. The hidden epidemic of pelvic floor dysfunction: achievable goals for improved prevention and treatment. Am J Obstet Gynecol. 2005;192:1488–95.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nEditor information\nEditors and Affiliations\nRights and permissions\nCopyright information\n© 2009 Humana Press, a part of Springer Science+Business Media, LLC, a part of Springer Science+Business Media, LLC\nAbout this chapter\nCite this chapter\nGargett, C.E., Schwab, K.E. (2009). The Endometrium: A Novel Source of Adult Stem/Progenitor Cells. In: Rajasekhar, V.K., Vemuri, M.C. (eds) Regulatory Networks in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60327-227-8_32\nDownload citation\nDOI: https://doi.org/10.1007/978-1-60327-227-8_32\nPublisher Name: Humana Press\nPrint ISBN: 978-1-60327-226-1\nOnline ISBN: 978-1-60327-227-8\neBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)","source_license":"CC0","license_restricted":false}