1932

Abstract

The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.

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2023-10-16
2024-12-12
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Literature Cited

  1. AAGL (Am. Assoc. Gynecol. Laparosc.) 2017. AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE). J. Minim. Invasive Gynecol. 24:695–705
    [Google Scholar]
  2. Abbas Y, Brunel LG, Hollinshead MS, Fernando RC, Gardner L et al. 2020. Generation of a three-dimensional collagen scaffold-based model of the human endometrium. Interface Focus 10:20190079
    [Google Scholar]
  3. Acosta Go V-A, Ibrahim Y 2022. Schistosomiasis induced Asherman's syndrome in a patient undergoing assisted reproductive technology (ART): a case report and literature review. Fertil. Steril. 118:e199
    [Google Scholar]
  4. Adoni A, Palti Z, Milwidsky A, Dolberg M. 1982. The incidence of intrauterine adhesions following spontaneous abortion. Int. J. Fertil. 27:117–18
    [Google Scholar]
  5. Aghajanova L, Horcajadas JA, Esteban FJ, Giudice LC. 2010. Bone marrow-derived human mesenchymal stem cell: potential progenitor of the endometrial stromal fibroblast. Biol. Reprod. 82:1076–87
    [Google Scholar]
  6. Ahn J, Yoon M-J, Hong S-H, Cha H, Lee D et al. 2021. Three-dimensional microengineered vascularised endometrium-on-a-chip. Hum. Reprod. 36:2720–31
    [Google Scholar]
  7. Alawadhi F, Du H, Cakmak H, Taylor HS. 2014. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman's syndrome. PLOS ONE 9:e96662
    [Google Scholar]
  8. Anderson WR, Davis J. 1968. Placental site involution. Am. J. Obstet. Gynecol. 102:23–33
    [Google Scholar]
  9. Aplin JD, Ruane PT. 2017. Embryo–epithelium interactions during implantation at a glance. J. Cell Sci. 130:15–22
    [Google Scholar]
  10. Appiah D, Nwabuo CC, Ebong IA, Wellons MF, Winters SJ. 2021. Trends in age at natural menopause and reproductive life span among US women, 1959–2018. JAMA 325:1328–30
    [Google Scholar]
  11. Arora R, Fries A, Oelerich K, Marchuk K, Sabeur K et al. 2016. Insights from imaging the implanting embryo and the uterine environment in three dimensions. Development 143:4749–54
    [Google Scholar]
  12. Asherman JG. 1948. Amenorrhoea traumatica (atretica). BJOG 55:23–30
    [Google Scholar]
  13. Ashworth MT, Moss CI, Kenyon WE. 1991. Granulomatous endometritis following hysteroscopic resection of the endometrium. Histopathology 18:185–87
    [Google Scholar]
  14. Baggish MS, Pauerstein CJ, Woodruff JD. 1967. Role of stroma in regeneration of endometrial epithelium. Am. J. Obstet. Gynecol. 99:459–65
    [Google Scholar]
  15. Barkley MS, Geschwind II, Bradford GE. 1979. The gestational pattern of estradiol, testosterone and progesterone secretion in selected strains of mice. Biol. Reprod. 20:733–38
    [Google Scholar]
  16. Bazaz-Malik G, Maheshwari B, Lal N. 1983. Tuberculous endometritis: a clinicopathological study of 1000 cases. BJOG 90:84–86
    [Google Scholar]
  17. Bellofiore N, Ellery S, Mamrot J, Walker D, Temple-Smith P, Dickinson H. 2016. First evidence of a menstruating rodent: the spiny mouse (Acomys cahirinus). Am. J. Obstet. Gynecol. 216:40.e1–11
    [Google Scholar]
  18. Benagiano G, Habiba M, Lippi D, Brosens IA. 2021. A history of neonatal uterine bleeding and its significance. Reprod. Med. 2:4171–84
    [Google Scholar]
  19. Benirschke K, Burton GJ, Baergen RN. 2012. Pathology of the Human Placenta Berlin, Ger: Springer
    [Google Scholar]
  20. Bergman P. 1961. Traumatic intra-uterine lesions. Acta Obstet. Gynecol. Scand. 40:1–39
    [Google Scholar]
  21. Brandon JM. 1990. Decidualization in the post-partum uterus of the mouse. J. Reprod. Fertil. 88:151–58
    [Google Scholar]
  22. Brandon JM. 1994. Distribution of macrophages in the mouse uterus from one day to three months after parturition, as defined by the immunohistochemical localization of the macrophage-restricted antigens F4/80 and macrosialin. Anat. Rec. 240:233–42
    [Google Scholar]
  23. Brasted M, White CA, Kennedy TG, Salamonsen LA. 2003. Mimicking the events of menstruation in the murine uterus. Biol. Reprod. 69:1273–80
    [Google Scholar]
  24. Bratincsák A, Brownstein MJ, Cassiani-Ingoni R, Pastorino S, Szalayova I et al. 2007. CD45-positive blood cells give rise to uterine epithelial cells in mice. Stem Cells 25:2820–26
    [Google Scholar]
  25. Brenner RM, Rudolph L, Matrisian L, Slayden OD. 1996. Non-human primate models: artificial menstrual cycles, endometrial matrix metalloproteinases and s.c. endometrial grafts. Hum. Reprod. 11:Suppl. 2150–64
    [Google Scholar]
  26. Brenner RM, Slayden OD. 2012. Molecular and functional aspects of menstruation in the macaque. Rev. Endocr. Metab. Disord. 13:309–18
    [Google Scholar]
  27. Budi EH, Schaub JR, Decaris M, Turner S, Derynck R. 2021. TGF-β as a driver of fibrosis: physiological roles and therapeutic opportunities. J. Pathol. 254:358–73
    [Google Scholar]
  28. Capmas P, Pourcelot A-G, Fernandez H. 2018. Are synechiae a complication of laparotomic myomectomy?. Reprod. Biomed. Online 36:450–54
    [Google Scholar]
  29. Carter AM. 2018. Classics revisited: C. J. van der Horst on pregnancy and menstruation in elephant shrews. Placenta 67:24–30
    [Google Scholar]
  30. Catalini L, Fedder J. 2020. Characteristics of the endometrium in menstruating species: lessons learned from the animal kingdom. Biol. Reprod. 102:1160–69
    [Google Scholar]
  31. Cervelló I, Gil-Sanchis C, Mas A, Delgado-Rosas F, Martínez-Conejero JA et al. 2010. Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PLOS ONE 5:e10964
    [Google Scholar]
  32. Cervelló I, Gil-Sanchis C, Mas A, Faus A, Sanz J et al. 2012. Bone marrow-derived cells from male donors do not contribute to the endometrial side population of the recipient. PLOS ONE 7:e30260
    [Google Scholar]
  33. Cervelló I, Gil-Sanchis C, Santamaría X, Cabanillas S, Díaz A et al. 2015. Human CD133+ bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome. Fertil. Steril. 104:1552–60.e3
    [Google Scholar]
  34. Cervelló I, Mas A, Gil-Sanchis C, Peris L, Faus A et al. 2011. Reconstruction of endometrium from human endometrial side population cell lines. PLOS ONE 6:e0021221
    [Google Scholar]
  35. Chan RWS, Schwab KE, Gargett CE. 2004. Clonogenicity of human endometrial epithelial and stromal cells. Biol. Reprod. 70:1738–50
    [Google Scholar]
  36. Cheung VC, Peng C-Y, Marinić M, Sakabe NJ, Aneas I et al. 2021. Pluripotent stem cell-derived endometrial stromal fibroblasts in a cyclic, hormone-responsive, coculture model of human decidua. Cell Rep. 35:109138
    [Google Scholar]
  37. Cousins FL, Murray A, Esnal A, Gibson DA, Critchley HOD, Saunders PTK. 2014. Evidence from a mouse model that epithelial cell migration and mesenchymal-epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation. PLOS ONE 9:e86378
    [Google Scholar]
  38. Critchley HOD, Maybin JA, Armstrong GM, Williams ARW. 2020. Physiology of the endometrium and regulation of menstruation. Physiol. Rev. 100:1149–79
    [Google Scholar]
  39. Darby IA, Hewitson TD. 2016. Hypoxia in tissue repair and fibrosis. Cell Tissue Res. 365:553–62
    [Google Scholar]
  40. Deans R, Abbott J. 2010. Review of intrauterine adhesions. J. Minim. Invasive Gynecol. 17:555–69
    [Google Scholar]
  41. Deno RA. 1937. Uterine macrophages in the mouse and their relation to involution. Am. J. Anat. 60:433–71
    [Google Scholar]
  42. Dickson MJ, Gruzdev A, DeMayo FJ. 2023. iCre recombinase expressed in the anti-Müllerian hormone receptor 2 gene causes global genetic modification in the mouse. Biol. Reprod. 108:575–83
    [Google Scholar]
  43. Dimitrov R, Timeva T, Kyurkchiev D, Stamenova M, Shterev A et al. 2008. Characterization of clonogenic stromal cells isolated from human endometrium. Reproduction 135:551–58
    [Google Scholar]
  44. Du H, Naqvi H, Taylor HS. 2012. Ischemia/reperfusion injury promotes and granulocyte-colony stimulating factor inhibits migration of bone marrow-derived stem cells to endometrium. Stem Cells Dev. 21:3324–31
    [Google Scholar]
  45. Du H, Taylor HS. 2007. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells 25:2082–86
    [Google Scholar]
  46. Eriksen J, Kaestel C. 1960. The incidence of uterine atresia after post-partum curettage. A follow-up examination of 141 patients. Dan. Med. Bull. 7:50–51
    [Google Scholar]
  47. Farhi J, Bar-Hava I, Homburg R, Dicker D, Ben-Rafael Z. 1993. Induced regeneration of endometrium following curettage for abortion: a comparative study. Hum. Reprod. 8:1143–44
    [Google Scholar]
  48. Ferenczy A. 1976. Studies on the cytodynamics of human endometrial regeneration. I. Scanning electron microscopy. Am. J. Obstet. Gynecol. 124:64–74
    [Google Scholar]
  49. Finn CA, Pope M. 1984. Vascular and cellular changes in the decidualized endometrium of the ovariectomized mouse following cessation of hormone treatment: a possible model for menstruation. J. Endocrinol. 100:295–300
    [Google Scholar]
  50. Foix A, Bruno RO, Davison T, Lema B. 1966. The pathology of postcurettage intrauterine adhesions. Am. J. Obstet. Gynecol. 96:1027–33
    [Google Scholar]
  51. Friedländer C. 1870. Physiologisch-anatomische Untersuchungen über den Uterus Leipzig, Ger: Simmel
    [Google Scholar]
  52. Friedler S, Margalioth EJ, Kafka I, Yaffe H. 1993. Incidence of post-abortion intra-uterine adhesions evaluated by hysteroscopy—a prospective study. Hum. Reprod. 8:442–44
    [Google Scholar]
  53. Fritsch H. 1894. Ein Fall von volligem Schwund ser Gebarmutterhohle nach Auskratzung. Centralblatt Gynäkologie 52:1337–39
    [Google Scholar]
  54. Fu D-J, De Micheli AJ, Bidarimath M, Ellenson LH, Cosgrove BD et al. 2020. Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma. Dis. Models Mech. 13:dmm047035
    [Google Scholar]
  55. Gan L, Duan H, Xu Q, Tang Y-Q, Li J-J et al. 2017. Human amniotic mesenchymal stromal cell transplantation improves endometrial regeneration in rodent models of intrauterine adhesions. Cytotherapy 19:603–16
    [Google Scholar]
  56. Gao Y, Duran S, Lydon JP, DeMayo FJ, Burghardt RC et al. 2015. Constitutive activation of transforming growth factor beta receptor 1 in the mouse uterus impairs uterine morphology and function. Biol. Reprod. 92:34
    [Google Scholar]
  57. Garcia-Alonso L, Handfield L-F, Roberts K, Nikolakopoulou K, Fernando RC et al. 2021. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro. Nat. Genet. 53:1698–711
    [Google Scholar]
  58. Gargett CE, Schwab KE, Zillwood RM, Nguyen HPT, Wu D. 2009. Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol. Reprod. 80:1136–45
    [Google Scholar]
  59. Garry R, Hart R, Karthigasu KA, Burke C. 2009. A re-appraisal of the morphological changes within the endometrium during menstruation: a hysteroscopic, histological and scanning electron microscopic study. Hum. Reprod. 24:1393–401
    [Google Scholar]
  60. Garry R, Hart R, Karthigasu KA, Burke C. 2010. Structural changes in endometrial basal glands during menstruation. BJOG 117:1175–85
    [Google Scholar]
  61. Ghosh A, Syed SM, Kumar M, Carpenter TJ, Teixeira JM et al. 2020. In vivo cell fate tracing provides no evidence for mesenchymal to epithelial transition in adult fallopian tube and uterus. Cell Rep. 31:107631
    [Google Scholar]
  62. Gibson DA, Simitsidellis I, Collins F, Saunders PTK. 2020. Androgens, oestrogens and endometrium: a fine balance between perfection and pathology. J. Endocrinol. 246:R75–93
    [Google Scholar]
  63. Gil-Sanchis C, Cervelló I, Mas A, Faus A, Pellicer A, Simón C. 2013. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) as a putative human endometrial stem cell marker. Mol. Hum. Reprod. 19:407–14
    [Google Scholar]
  64. Gilman AR, Dewar KM, Rhone SA, Fluker MR. 2016. Intrauterine adhesions following miscarriage: look and learn. J. Obstet. Gynaecol. Can. 38:453–57
    [Google Scholar]
  65. Golebiewska A, Brons NHC, Bjerkvig R, Niclou SP. 2011. Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell 8:136–47
    [Google Scholar]
  66. Gray CA, Bartol FF, Tarleton BJ, Wiley AA, Johnson GA et al. 2001. Developmental biology of uterine glands. Biol. Reprod. 65:1311–23
    [Google Scholar]
  67. Haig D. 1995. Whitridge Williams’ obstetrics. Am. J. Obstet. Gynecol. 173:1351
    [Google Scholar]
  68. Hald H. 1949. On uterine atresia consequent to curettage. Acta Obstet. Gynecol. Scand. 28:169–74
    [Google Scholar]
  69. Hanstede MMF, van der Meij E, Goedemans L, Emanuel MH. 2015. Results of centralized Asherman surgery, 2003–2013. Fertil. Steril. 104:1561–68.e1
    [Google Scholar]
  70. Hartman CG. 1944. Regeneration of the monkey uterus after surgical removal of the endometrium and accidental endometriosis. West J. Surg. Obstet. Gynecol. 52:87–102
    [Google Scholar]
  71. Hemberger M, Hanna CW, Dean W. 2020. Mechanisms of early placental development in mouse and humans. Nat. Rev. Genet. 21:27–43
    [Google Scholar]
  72. Henderson NC, Rieder F, Wynn TA. 2020. Fibrosis: from mechanisms to medicines. Nature 587:555–66
    [Google Scholar]
  73. Howlader N, Noone A, Krapcho M, Miller D, Brest A et al. 2021. SEER cancer statistics review, 1975–2018 Rep. Natl. Cancer Inst. Bethesda, MD: https://seer.cancer.gov/csr/1975_2018/
    [Google Scholar]
  74. Hsu YC. 2015. Theory and practice of lineage tracing. Stem Cells 33:3197–204
    [Google Scholar]
  75. Hu J, Song K, Zhang J, Zhang Y, Tan B-Z. 2019. Effects of menstrual blood-derived stem cells on endometrial injury repair. Mol. Med. Rep. 19:813–20
    [Google Scholar]
  76. Huang C-C, Orvis GD, Wang Y, Behringer RR. 2012. Stromal-to-epithelial transition during postpartum endometrial regeneration. PLOS ONE 7:e44285
    [Google Scholar]
  77. Ikoma T, Kyo S, Maida Y, Ozaki S, Takakura M et al. 2009. Bone marrow–derived cells from male donors can compose endometrial glands in female transplant recipients. Am. J. Obstet. Gynecol. 201:608.e1–8
    [Google Scholar]
  78. Isley MM 2021. Postpartum care and long-term health considerations. Gabbe's Obstetrics: Normal and Problem Pregnancies M Landon, H Galan, E Jauniaux, D Driscoll, V Berghella et al.459–74. Philadelphia, PA: Elsevier. , 8th ed..
    [Google Scholar]
  79. Jabbour HN, Kelly RW, Fraser HM, Critchley HOD. 2006. Endocrine regulation of menstruation. Endocr. Rev. 27:17–46
    [Google Scholar]
  80. Jamaluddin MFB, Ghosh A, Ingle A, Mohammed R, Ali A et al. 2022. Bovine and human endometrium-derived hydrogels support organoid culture from healthy and cancerous tissues. PNAS 119:e2208040119
    [Google Scholar]
  81. Jensen PA, Stromme WB. 1972. Amenorrhea secondary to puerperal curettage (Asherman's syndrome). Am. J. Obstet. Gynecol. 113:150–57
    [Google Scholar]
  82. Jin S 2019. Bipotent stem cells support the cyclical regeneration of endometrial epithelium of the murine uterus. PNAS 116:6848–57
    [Google Scholar]
  83. Johannisson E, Fournier K, Riotton G. 1981. Regeneration of the human endometrium and presence of inflammatory cells following diagnostic curettage. Acta Obstet. Gynecol. Scand. 60:451–57
    [Google Scholar]
  84. Johary J, Xue M, Zhu X, Xu D, Velu PP. 2014. Efficacy of estrogen therapy in patients with intrauterine adhesions: systematic review. J. Minim. Invasive Gynecol. 21:44–54
    [Google Scholar]
  85. Johnson FW. 1900. Steam in the treatment of chronic, hyperplastic, and senile endometritis, putrid abortion and puerperal sepsis. Boston Med. Surg. J. 142:269–74
    [Google Scholar]
  86. Jonkman MF, Kauer FM, Nieuwenhuis P, Molenaar I. 1986. Segmental uterine horn replacement in the rat using a biodegradable microporous synthetic tube. Artif. Organs 10:475–80
    [Google Scholar]
  87. Kaitu'u-Lino TJ, Morison NB, Salamonsen LA. 2007. Estrogen is not essential for full endometrial restoration after breakdown: lessons from a mouse model. Endocrinology 148:5105–11
    [Google Scholar]
  88. Kaitu'u-Lino TJ, Ye L, Gargett CE. 2010. Reepithelialization of the uterine surface arises from endometrial glands: evidence from a functional mouse model of breakdown and repair. Endocrinology 151:3386–95
    [Google Scholar]
  89. Kato K, Yoshimoto M, Kato K, Adachi S, Yamayoshi A et al. 2007. Characterization of side-population cells in human normal endometrium. Hum. Reprod. 22:1214–23
    [Google Scholar]
  90. Kelly RW, King AE, Critchley HO. 2001. Cytokine control in human endometrium. Reproduction 121:3–19
    [Google Scholar]
  91. Kilic S, Yuksel B, Pinarli F, Albayrak A, Boztok B, Delibasi T. 2014. Effect of stem cell application on Asherman syndrome, an experimental rat model. J. Assist. Reprod. Genet. 31:975–82
    [Google Scholar]
  92. Kirkwood PM, Gibson DA, Shaw I, Dobie R, Kelepouri O et al. 2022. Single cell RNA sequencing and lineage tracing confirm mesenchyme to epithelial transformation (MET) contributes to repair of the endometrium at menstruation. eLife 11:e77663
    [Google Scholar]
  93. Kirkwood PM, Gibson DA, Smith JR, Wilson-Kanamori JR, Kelepouri O et al. 2021. Single-cell RNA sequencing redefines the mesenchymal cell landscape of mouse endometrium. FASEB J. 35:e21285
    [Google Scholar]
  94. Krolikowski A, Janowski K, Larsen JVM. 1995. Asherman syndrome caused by schistosomiasis. Obstet. Gynecol. 85:898–99
    [Google Scholar]
  95. Kuokkanen S, Zhu L, Pollard JW. 2017. Xenografted tissue models for the study of human endometrial biology. Differentiation 98:62–69
    [Google Scholar]
  96. Leung RK, Lin Y, Liu Y. 2020. Recent advances in understandings towards pathogenesis and treatment for intrauterine adhesion and disruptive insights from single-cell analysis. Reprod. Sci. 28:1812–26
    [Google Scholar]
  97. Lewis PR, Galvin PM, Short RV. 1987. Salivary oestriol and progesterone concentrations in women during late pregnancy, parturition and the puerperium. J. Endocrinol. 115:177–81
    [Google Scholar]
  98. Li X, Kodithuwakku SP, Chan RWS, Yeung WSB, Yao Y et al. 2022. Three-dimensional culture models of human endometrium for studying trophoblast-endometrium interaction during implantation. Reprod. Biol. Endocrinol. 20:120
    [Google Scholar]
  99. Li X, Sun H, Lin N, Hou X, Wang J et al. 2011. Regeneration of uterine horns in rats by collagen scaffolds loaded with collagen-binding human basic fibroblast growth factor. Biomaterials 32:8172–81
    [Google Scholar]
  100. Liang S, Huang Y, Xia Y, Liang S, Wu Q, Zhi Z. 2022. Animal models in intrauterine adhesion research. J. Obstet. Gynaecol. 42:83409–15
    [Google Scholar]
  101. Lipschutz JH, Fukami H, Yamamoto M, Tatematsu M, Sugimura Y et al. 1999. Clonality of urogenital organs as determined by analysis of chimeric mice. Cells Tissues Organs 165:57–66
    [Google Scholar]
  102. Lisa JR, Gioia JD, Rubin IC. 1954. Observations on the interstitial portion of the fallopian tube. Surg. Gynecol. Obstet. 99:159–69
    [Google Scholar]
  103. Liu F, Zhu Z-J, Li P, He Y-L. 2013. Creation of a female rabbit model for intrauterine adhesions using mechanical and infectious injury. J. Surg. Res. 183:296–303
    [Google Scholar]
  104. Liu L, Yang H, Guo Y, Yang G, Chen Y. 2019. The impact of chronic endometritis on endometrial fibrosis and reproductive prognosis in patients with moderate and severe intrauterine adhesions: a prospective cohort study. Fertil. Steril. 111:1002–10.e2
    [Google Scholar]
  105. Liu T, Shi F, Ying Y, Chen Q, Tang Z, Lin H. 2020. Mouse model of menstruation: an indispensable tool to investigate the mechanisms of menstruation and gynaecological diseases. Mol. Med. Rep. 22:4463–74
    [Google Scholar]
  106. Liu T, Zhang L, Joo D, Sun S-C. 2017. NF-κB signaling in inflammation. Signal Transduct. Target. Ther. 2:17023
    [Google Scholar]
  107. Liu Y, Tal R, Pluchino N, Mamillapalli R, Taylor HS. 2018. Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J. Cell. Mol. Med. 22:67–76
    [Google Scholar]
  108. Liu Z, Doan QV, Blumenthal P, Dubois RW. 2007. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health 10:183–94
    [Google Scholar]
  109. Longinotti MK, Jacobson GF, Hung Y-Y, Learman LA. 2008. Probability of hysterectomy after endometrial ablation. Obstet. Gynecol. 112:1214–20
    [Google Scholar]
  110. Ludwig H. 1971. Surface structure of the human term placenta and of the uterine wall post partum in the screen scan electron microscope. Am. J. Obstet. Gynecol. 111:328–44
    [Google Scholar]
  111. Ludwig H, Metzger H. 1976. The re-epithelization of endometrium after menstrual desquamation. Arch. Gynakol. 221:51–60
    [Google Scholar]
  112. Ludwig H, Spornitz UM. 1991. Microarchitecture of the human endometrium by scanning electron microscopy: menstrual desquamation and remodeling. Ann. N.Y. Acad. Sci. 622:28–46
    [Google Scholar]
  113. Marbaix E, Kokorine I, Moulin P, Donnez J, Eeckhout Y, Courtoy PJ. 1996. Menstrual breakdown of human endometrium can be mimicked in vitro and is selectively and reversibly blocked by inhibitors of matrix metalloproteinases. PNAS 93:9120–25
    [Google Scholar]
  114. March CM. 2011a. Asherman's syndrome. Semin. Reprod. Med. 29:83–94
    [Google Scholar]
  115. March CM. 2011b. Management of Asherman's syndrome. Reprod. Biomed. Online 23:63–76
    [Google Scholar]
  116. Markee JE. 1940. Menstruation in intraocular endometrial transplants in the rhesus monkey. Contrib. Embryol. Carnegie Inst. Wash. 28:219–308
    [Google Scholar]
  117. Martinez GM. 2020. Trends and patterns in menarche in the United States: 1995 through 2013–2017 Natl. Health Stat. Rep. 146 Natl. Cent. Health Stat. Hyattsville, MD:
    [Google Scholar]
  118. Masuda H, Anwar SS, Bühring H-J, Rao JR, Gargett CE. 2012. A novel marker of human endometrial mesenchymal stem-like cells. Cell Transplant. 21:2201–14
    [Google Scholar]
  119. McLennan CE. 1969. Endometrial regeneration after curettage. Am. J. Obstet. Gynecol. 104:185–94
    [Google Scholar]
  120. Metcalf MG, Donald RA, Livesey JH. 1981. Pituitary-ovarian function in normal women during the menopausal transition. Clin. Endocrinol. 14:245–55
    [Google Scholar]
  121. Moore L, Leongamornlert D, Coorens THH, Sanders MA, Ellis P et al. 2020. The mutational landscape of normal human endometrial epithelium. Nature 580:640–46
    [Google Scholar]
  122. Morelli SS, Rameshwar P, Goldsmith LT. 2013. Experimental evidence for bone marrow as a source of nonhematopoietic endometrial stromal and epithelial compartment cells in a murine model. Biol. Reprod. 89:7
    [Google Scholar]
  123. Nathan C, Ding A. 2010. Nonresolving inflammation. Cell 140:871–82
    [Google Scholar]
  124. Netter A, Musset R, Lambert A, Salomon Y, Montbazet G. 1955. Symphyses endo-utérines tuberculeuses: un syndrome anatomo-clinique et radiologique caractéristique. Gynecol. Obstet. 54:19–36
    [Google Scholar]
  125. Nguyen HPT, Xiao L, Deane JA, Tan K-S, Cousins FL et al. 2017. N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays. Hum. Reprod. 32:2254–68
    [Google Scholar]
  126. Ning J, Zhang H, Yang H. 2018. MicroRNA-326 inhibits endometrial fibrosis by regulating TGF-β1/Smad3 pathway in intrauterine adhesions. Mol. Med. Rep. 18:2286–92
    [Google Scholar]
  127. Nogales-Ortiz F, Puerta J, Nogales FF. 1978. The normal menstrual cycle: chronology and mechanism of endometrial desquamation. Obstet. Gynecol. 51:259–64
    [Google Scholar]
  128. Novak E, Te Linde RW. 1924. The endometrium of the menstruating uterus. JAMA 83:900–6
    [Google Scholar]
  129. Ong YR, Cousins FL, Yang X, Mushafi AAAA, Breault DT et al. 2018. Bone marrow stem cells do not contribute to endometrial cell lineages in chimeric mouse models. Stem Cells 36:91–102
    [Google Scholar]
  130. Onoglu A, Taskin O, Inal M, Sadik S, Simsek M et al. 2007. Comparison of the long-term histopathologic and morphologic changes after endometrial rollerball ablation and resection: a prospective randomized trial. J. Minim. Invasive Gynecol. 14:39–42
    [Google Scholar]
  131. Patterson A, Pru J. 2013. Long-term label retaining cells localize to distinct regions within the female reproductive epithelium. Cell Cycle 12:2888–98
    [Google Scholar]
  132. Patterson AL, Zhang L, Arango NA, Teixeira J, Pru JK. 2013. Mesenchymal-to-epithelial transition contributes to endometrial regeneration following natural and artificial decidualization. Stem Cells Dev. 22:964–74
    [Google Scholar]
  133. Polishuk WZ, Siew FP, Gordon R, Lebenshart P. 1977. Vascular changes in traumatic amenorrhea and hypomenorrhea. Int. J. Fertil. 22:189–92
    [Google Scholar]
  134. Rabau E, David A. 1963. Intrauterine adhesions, etiology, prevention, and treatment. Obstet. Gynecol. 22:626–29
    [Google Scholar]
  135. Rasweiler JJ, Debonilla H. 1992. Menstruation in short-tailed fruit bats (Carollia spp.). J. Reprod. Fertil. 95:231–48
    [Google Scholar]
  136. Rockey DC, Bell PD, Hill JA. 2015. Fibrosis—a common pathway to organ injury and failure. N. Engl. J. Med. 372:1138–49
    [Google Scholar]
  137. Rodgers WH, Matrisian LM, Giudice LC, Dsupin B, Cannon P et al. 1994. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J. Clin. Investig. 94:946–53
    [Google Scholar]
  138. Römer T. 1994. Post-abortion hysteroscopy: a method for early diagnosis of congenital and acquired intrauterine causes of abortions. Eur. J. Obstet. Gynecol. Reprod. Biol. 57:171–73
    [Google Scholar]
  139. Rudolph M, Döcke W-D, Müller A, Menning A, Röse L et al. 2012. Induction of overt menstruation in intact mice. PLOS ONE 7:e32922
    [Google Scholar]
  140. Sahin Ersoy G, Zolbin MM, Cosar E, Moridi I, Mamillapalli R, Taylor HS. 2017. CXCL12 promotes stem cell recruitment and uterine repair after injury in Asherman's syndrome. Mol. Ther. Methods Clin. Dev. 4:169–77
    [Google Scholar]
  141. Salma U, Xue M, Ali Sheikh MS, Guan X, Xu B et al. 2016. Role of transforming growth factor-β1 and smads signaling pathway in intrauterine adhesion. Mediat. Inflamm. 2016:e4158287
    [Google Scholar]
  142. Santamaria X, Cabanillas S, Cervelló I, Arbona C, Raga F et al. 2016. Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman's syndrome and endometrial atrophy: a pilot cohort study. Hum. Reprod. 31:1087–96
    [Google Scholar]
  143. Santamaria X, Roson B, Perez R, Venkatesan N, Gonzalez-Fernandez J et al. 2022. Decoding the endometrial niche of Asherman's Syndrome at single-cell resolution. medRxiv 2022.10.21.22281346
  144. Schaefer G. 1976. Female genital tuberculosis. Clin. Obstet. Gynecol. 19:223–39
    [Google Scholar]
  145. Schenker JG, Margalioth EJ. 1982. Intrauterine adhesions: an updated appraisal. Fertil. Steril. 37:593–610
    [Google Scholar]
  146. Schenker JG, Nicosia SV, Polishuk WZ, Garcia CR. 1975. An in vitro fibroblast-enriched sponge preparation for induction of intrauterine adhesions. Isr. J. Med. Sci. 11:849–51
    [Google Scholar]
  147. Schenker JG, Polishuk WZ. 1972. Regeneration of rabbit endometrium after cryosurgery. Obstet. Gynecol. 40:638–45
    [Google Scholar]
  148. Schenker JG, Polishuk WZ. 1973. Regeneration of rabbit endometrium following intrauterine instillation of chemical agents. Gynecol. Investig. 4:11–13
    [Google Scholar]
  149. Schenker JG, Polishuk WZ, Sacks MI. 1973a. Regeneration of the endometrium in rabbits after curettage. I. Pretreatment with estrogens. J. Reprod. Med. 11:43–48
    [Google Scholar]
  150. Schenker JG, Polishuk WZ, Sacks MI. 1973b. Regeneration of the endometrium in rabbits after curettage. II. Pretreatment with progesterone. J. Reprod. Med. 11:49–57
    [Google Scholar]
  151. Schenker JG, Sacks MI, Polishuk WZ. 1971. I. Regeneration of rabbit endometrium following curettage. Am. J. Obstet. Gynecol. 111:970–78
    [Google Scholar]
  152. Schwab KE, Chan RWS, Gargett CE. 2005. Putative stem cell activity of human endometrial epithelial and stromal cells during the menstrual cycle. Fertil. Steril. 84:1124–30
    [Google Scholar]
  153. Schwab KE, Gargett CE. 2007. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum. Reprod. 22:2903–11
    [Google Scholar]
  154. Seishima R, Leung C, Yada S, Murad KBA, Tan LT et al. 2019. Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development. Nat. Commun. 10:5378
    [Google Scholar]
  155. Sharma JB, Roy KK, Pushparaj M, Gupta N, Jain SK et al. 2008. Genital tuberculosis: an important cause of Asherman's syndrome in India. Arch. Gynecol. Obstet. 277:37–41
    [Google Scholar]
  156. Sharman A. 1953. Post-partum regeneration of the human endometrium. J. Anat. 87:1–10
    [Google Scholar]
  157. Shavell VI, Diamond MP, Senter JP, Kruger ML, Johns DA. 2012. Hysterectomy subsequent to endometrial ablation. J. Minim. Invasive Gynecol. 19:459–64
    [Google Scholar]
  158. Silvernagel SW, Harshbarger KE, Shevlin DW. 1997. Postoperative granulomas of the endometrium: histological features after endometrial ablation. Ann. Diagn. Pathol. 1:82–90
    [Google Scholar]
  159. Slayden OD, Brenner RM. 2006. A critical period of progesterone withdrawal precedes menstruation in macaques. Reprod. Biol. Endocrinol. 4:Suppl. 1S6
    [Google Scholar]
  160. Smid I, Bedö T. 1978. Curettage during puerperium and its late consequences. Zentralbl. Gynakol. 100:916–20
    [Google Scholar]
  161. Song T, Zhao X, Sun H, Xa Li, Lin N et al. 2015. Regeneration of uterine horns in rats using collagen scaffolds loaded with human embryonic stem cell-derived endometrium-like cells. Tissue Eng. Part A 21:353–61
    [Google Scholar]
  162. Spooner MK, Lenis YY, Watson R, Jaimes D, Patterson AL. 2021. The role of stem cells in uterine involution. Reproduction 161:R61–77
    [Google Scholar]
  163. Spooner-Harris M, Kerns K, Zigo M, Sutovsky P, Balboula A, Patterson AL. 2022. A re-appraisal of mesenchymal-epithelial transition (MET) in endometrial epithelial remodeling. Cell Tissue Res. 391:393–408
    [Google Scholar]
  164. Stamer S. 1946. Partial and total atresia of the uterus after excochleation. Acta Obstet. Gynecol. Scand. 26:263–97
    [Google Scholar]
  165. Stewart CA, Stewart MD, Wang Y, Mullen RD, Kircher BK et al. 2022. Chronic estrus disrupts uterine gland development and homeostasis. Endocrinology 163:bqac011
    [Google Scholar]
  166. Strug MR, Su RW, Kim TH, Mauriello A, Ticconi C et al. 2018. RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss. FASEB J. 32:2452–66
    [Google Scholar]
  167. Sugimoto O. 1978. Diagnostic and therapeutic hysteroscopy for traumatic intrauterine adhesions. Am. J. Obstet. Gynecol. 131:539–47
    [Google Scholar]
  168. Swain M, Kulkarni AD. 2021. Endometrium at menopause: the pathologist's view. J. Midlife Health 12:310–15
    [Google Scholar]
  169. Syed SM, Kumar M, Ghosh A, Tomasetig F, Ali A et al. 2020. Endometrial Axin2+ cells drive epithelial homeostasis, regeneration, and cancer following oncogenic transformation. Cell Stem Cell 26:64–80.e13
    [Google Scholar]
  170. Tal R, Kisa J, Abuwala N, Kliman HJ, Shaikh S et al. 2021. Bone marrow-derived progenitor cells contribute to remodeling of the postpartum uterus. Stem Cells 39:1489–505
    [Google Scholar]
  171. Tal R, Liu Y, Pluchino N, Shaikh S, Mamillapalli R, Taylor HS. 2016. A murine 5-fluorouracil-based submyeloablation model for the study of bone marrow-derived cell trafficking in reproduction. Endocrinology 157:3749–59
    [Google Scholar]
  172. Tal R, Shaikh S, Pallavi P, Tal A, López-Giráldez F et al. 2019. Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy. PLOS Biol. 17:e3000421
    [Google Scholar]
  173. Tanaka M, Kyo S, Kanaya T, Yatabe N, Nakamura M et al. 2003. Evidence of the monoclonal composition of human endometrial epithelial glands and mosaic pattern of clonal distribution in luminal epithelium. Am. J. Pathol. 163:295–301
    [Google Scholar]
  174. Tang Y-Q, Gan L, Xu Q, Wang S, Li J-J, Duan H. 2016. Effects of human umbilical cord mesenchymal stem cells on intrauterine adhesions in a rat model. Int. J. Clin. Exp. Pathol. 9:12119–29
    [Google Scholar]
  175. Taskin O, Onoglu A, Inal M, Turan E, Sadik S et al. 2002. Long-term histopathologic and morphologic changes after thermal endometrial ablation. J. Am. Assoc. Gynecol. Laparosc. 9:186–90
    [Google Scholar]
  176. Taveau JW, Tartaglia M, Buchannan D, Smith B, Koenig G et al. 2004. Regeneration of uterine horn using porcine small intestinal submucosa grafts in rabbits. J. Investig. Surg. 17:81–92
    [Google Scholar]
  177. Taylor HS. 2004. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA 292:81–85
    [Google Scholar]
  178. Tempest N, Hill CJ, Maclean A, Marston K, Powell SG et al. 2022. Novel microarchitecture of human endometrial glands: implications in endometrial regeneration and pathologies. Hum. Reprod. Update 28:153–71
    [Google Scholar]
  179. Tempest N, Jansen M, Baker AM, Hill CJ, Hale M et al. 2020. Histological 3D reconstruction and in vivo lineage tracing of the human endometrium. J. Pathol. 251:440–51
    [Google Scholar]
  180. Tempest N, Maclean A, Hapangama DK. 2018. Endometrial stem cell markers: current concepts and unresolved questions. Int. J. Mol. Sci. 19:3240
    [Google Scholar]
  181. Toaff R, Ballas S. 1978. Traumatic hypomenorrhea-amenorrhea (Asherman's syndrome). Fertil. Steril. 30:379–87
    [Google Scholar]
  182. Tresserra F, Grases P, Ubeda A, Pascual MA, Grases PJ, Labastida R. 1999. Morphological changes in hysterectomies after endometrial ablation. Hum. Reprod. 14:1473–77
    [Google Scholar]
  183. Tsuji S, Yoshimoto M, Takahashi K, Noda Y, Nakahata T, Heike T. 2008. Side population cells contribute to the genesis of human endometrium. Fertil. Steril. 90:1528–37
    [Google Scholar]
  184. Turnbull LW, Jumaa A, Bowsley SJ, Dhawan S, Horsman A, Killick SR. 1997. Magnetic resonance imaging of the uterus after endometrial resection. BJOG 104:934–38
    [Google Scholar]
  185. Valentijn AJ, Palial K, Al-lamee H, Tempest N, Drury J et al. 2013. SSEA-1 isolates human endometrial basal glandular epithelial cells: phenotypic and functional characterization and implications in the pathogenesis of endometriosis. Hum. Reprod. 28:2695–708
    [Google Scholar]
  186. Van De Water L, Varney S, Tomasek JJ. 2013. Mechanoregulation of the myofibroblast in wound contraction, scarring, and fibrosis: opportunities for new therapeutic intervention. Adv. Wound Care 2:122–41
    [Google Scholar]
  187. Van Der Horst CJ. 1954. Elephantulus going into anoestrus menstruation and abortion. Phil. Trans. R. Soc. B 238:27–61
    [Google Scholar]
  188. Ventolini G, Zhang M, Gruber J. 2004. Hysteroscopy in the evaluation of patients with recurrent pregnancy loss: a cohort study in a primary care population. Surg. Endosc. 18:1782–84
    [Google Scholar]
  189. Wang Q, Xu X, He B, Li Y, Chen X, Wang J. 2013. A critical period of progesterone withdrawal precedes endometrial breakdown and shedding in mouse menstrual-like model. Human Reprod. 28:1670–78
    [Google Scholar]
  190. Wang W, Vilella F, Alama P, Moreno I, Mignardi M et al. 2020. Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle. Nat. Med. 26:1644–53
    [Google Scholar]
  191. Wang X, Ma N, Sun Q, Huang C, Liu Y, Luo X. 2017. Elevated NF-κB signaling in Asherman syndrome patients and animal models. OncoTargets Ther. 8:15399–406
    [Google Scholar]
  192. Welsh AO, Enders AC. 1983. Occlusion and reformation of the rat uterine lumen during pregnancy. Am. J. Anat. 167:463–77
    [Google Scholar]
  193. Westendorp IC, Ankum WM, Mol BW, Vonk J. 1998. Prevalence of Asherman's syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion. Hum. Reprod. 13:3347–50
    [Google Scholar]
  194. Williams JW. 1931. Regeneration of the uterine mucosa after delivery, with especial reference to the placental site. Am. J. Obstet. Gynecol. 22:664–96
    [Google Scholar]
  195. Winkler I, Tolkachov A, Lammers F, Lacour P, Schneider N et al. 2022. The function and decline of the female reproductive tract at single-cell resolution. bioRxiv 2022.10.26.513823. https://doi.org/10.1101/2022.10.26.513823
    [Crossref]
  196. Wolff EF, Uchida N, Donahue RE, Metzger ME, Hsieh MM et al. 2013. Peripheral blood stem cell transplants do not result in endometrial stromal engraftment. Fertil. Steril. 99:526–32.e2
    [Google Scholar]
  197. Wood GA, Fata JE, Watson KLM, Khokha R. 2007. Circulating hormones and estrous stage predict cellular and stromal remodeling in murine uterus. Reproduction 133:1035–44
    [Google Scholar]
  198. Wortman M. 2017. Late-onset endometrial ablation failure. Case Rep. . Women's Health 15:11–28
    [Google Scholar]
  199. Wyss P, Steiner R, Liaw LH, Wyss MT, Ghazarians A et al. 1996. Uterus and endometrium: regeneration processes in rabbit endometrium: a photodynamic therapy model. Hum. Reprod. 11:1992–97
    [Google Scholar]
  200. Xiao S, Wan Y, Xue M, Zeng X, Xiao F et al. 2014. Etiology, treatment, and reproductive prognosis of women with moderate-to-severe intrauterine adhesions. Int. J. Gynaecol. Obstet. 125:121–24
    [Google Scholar]
  201. Xu X, Chen X, Li Y, Cao H, Shi C et al. 2013. Cyclooxygenase-2 regulated by the nuclear factor-κB pathway plays an important role in endometrial breakdown in a female mouse menstrual-like model. Endocrinology 154:2900–11
    [Google Scholar]
  202. Xue X, Chen Q, Zhao G, Zhao J-Y, Duan Z, Zheng P-S. 2015. The overexpression of TGF-β and CCN2 in intrauterine adhesions involves the NF-κB signaling pathway. PLOS ONE 10:e0146159
    [Google Scholar]
  203. Yaffe H, Ron M, Polishuk WZ. 1978. Amenorrhea, hypomenorrhea, and uterine fibrosis. Am. J. Obstet. Gynecol. 130:599–601
    [Google Scholar]
  204. Yamaguchi M, Yoshihara K, Suda K, Nakaoka H, Yachida N et al. 2021. Three-dimensional understanding of the morphological complexity of the human uterine endometrium. iScience 24:102258
    [Google Scholar]
  205. Yin M, Zhou HJ, Lin C, Long L, Yang X et al. 2019. CD34+ KLF4+ stromal stem cells contribute to endometrial regeneration and repair. Cell Rep. 27:2709–24.e3
    [Google Scholar]
  206. Yin Z, Wang J, Cui W, Tong C. 2023. Advanced biomaterials for promoting endometrial regeneration. Adv. Healthcare Mater. https://doi.org/10.1002/adhm.202202490
    [Google Scholar]
  207. Young RE, Huh DD. 2021. Organ-on-a-chip technology for the study of the female reproductive system. Adv. Drug. Deliv. Rev. 173:461–78
    [Google Scholar]
  208. Yuan J, Deng W, Cha J, Sun X, Borg J-P, Dey SK. 2018. Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat. Commun. 9:603
    [Google Scholar]
  209. Zhang ET, Wells KL, Steinmetz L, Baker JC. 2022. Uterine injury during diestrus leads to embryo spacing defects and perturbations in the COX pathway in subsequent pregnancies. bioRxiv 2022.03.15.484521. https://doi.org/10.1101/2022.03.15.484521
  210. Zondervan KT, Becker CM, Missmer SA. 2020. Endometriosis. N. Engl. J. Med. 382:1244–56
    [Google Scholar]
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