Immunolocalization of stem/progenitor cell biomarkers Oct-4, C-kit and Musashi-1 in endometriotic lesions

Background Human endometrium harbors stem/progenitor cells (SPCs) that may contribute to the establishment of endometriosis when seeded outside the uterus. Oct-4, C-kit and Musashi-1 are some of the many proteins used to characterize SPCs, but their association with endometriosis is uncertain.

and Design In this study, specimens of normal endometrium (n = 12), eutopic endometrium from women with endometriosis (n = 9), superficial peritoneal endometriosis (SUP, n = 12) and deep endometriosis (DE, n = 13) lesions were evaluated for localization and intensity of immunostaining for Oct-4, C-kit and Musashi-1.

The three markers were abundantly expressed in normal endometrium, eutopic endometrium from endometriosis patients, SUP and DE specimens. Oct-4 and C-kit expression did not vary across groups as regards intensity or frequency. C-kit staining signal was seldom detected in vascular endothelium of normal or eutopic endometrium from endometriosis patients; however, it was positive in 67% of the SUP lesions and in 25% of the DE lesions (p = 0.042). Musashi-1 was expressed in some endometriotic glands as cell clusters, but its signal was similar between the four types of tissue (p = 0.971)

The wide distribution of Oct-4, C-kit and Musashi-1 in endometria of patients with and without endometriosis and in SUP and DE endometriotic lesions suggests that these markers are not suitable for the in situ characterization of endometrial SPCs and should not be taken as surrogates for the study of SPCs in the pathogenesis of endometriosis. Similar content being viewed by others Data availability Data will be available from the corresponding author upon reasonable request.

Bulun SE et al (2019) Endometriosis. Endocr Rev 40:1048–1079. https://doi.org/10.1210/er.2018-00242 Gargett CE, Schwab KE, Deane JA (2016) Endometrial stem/progenitor cells: the first 10 years. Hum Reprod Update 22:137–163. https://doi.org/10.1093/humupd/dmv051 Masuda H, Schwab KE, Filby CE, Tan CSC, Tsaltas J, Weston GC, Gargett CE (2021) Endometrial stem/progenitor cells in menstrual blood and peritoneal fluid of women with and without endometriosis. Reprod Biomed Online. https://doi.org/10.1016/j.rbmo.2021.04.008 Liu Y et al (2020) Biological characteristics of endometriotic mesenchymal stem cells isolated from ectopic lesions of patients with endometriosis. Stem Cell Res Ther 11:346. https://doi.org/10.1186/s13287-020-01856-8 Silveira CG et al (2012) Common chromosomal imbalances and stemness-related protein expression markers in endometriotic lesions from different anatomical sites: the potential role of stem cells. Hum Reprod 27:3187–3197. https://doi.org/10.1093/humrep/des282 Sundaresan Y, Veerappan M, Ramasamy KS, Chidambaranathan GP (2019) Identification, quantification and age-related changes of human trabecular meshwork stem cells. Eye Vis (Lond, Engl) 6:31. https://doi.org/10.1186/s40662-019-0156-z Rux DR et al (2016) Regionally restricted Hox function in adult bone marrow multipotent mesenchymal stem/stromal cells. Dev Cell 39:653–666. https://doi.org/10.1016/j.devcel.2016.11.008 Jerabek S, Merino F, Schöler HR, Cojocaru V (2014) OCT4: dynamic DNA binding pioneers stem cell pluripotency. Biochimica et Biophysica Acta 1839:138–154. https://doi.org/10.1016/j.bbagrm.2013.10.001 Sogo S et al (1997) Induction of c-kit molecules on human CD34+/c-kit < low cells: evidence for CD34+/c-kit < low cells as primitive hematopoietic stem cells. Stem Cells (Dayton, Ohio) 15:420–429. https://doi.org/10.1002/stem.150420 Cervelló I, Martínez-Conejero JA, Horcajadas JA, Pellicer A, Simón C (2007) Identification, characterization and co-localization of label-retaining cell population in mouse endometrium with typical undifferentiated markers. Hum Reprod 22:45–51. https://doi.org/10.1093/humrep/del332 Matthai C et al (2006) Oct-4 expression in human endometrium. Mol Hum Reprod 12:7–10. https://doi.org/10.1093/molehr/gah254 Bentz EK, Kenning M, Schneeberger C, Kolbus A, Huber JC, Hefler LA, Tempfer CB (2010) OCT-4 expression in follicular and luteal phase endometrium: a pilot study. Reprod Biol Endocrinol 8:38. https://doi.org/10.1186/1477-7827-8-38 Cho NH, Park YK, Kim YT, Yang H, Kim SK (2004) Lifetime expression of stem cell markers in the uterine endometrium. Fertil Steril 81:403–407. https://doi.org/10.1016/j.fertnstert.2003.07.015 Götte M et al (2011) The adult stem cell marker Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via Notch-1 and p21WAF1/CIP1. Int J Cancer 129:2042–2049. https://doi.org/10.1002/ijc.25856 Schüring AN et al (2018) The endometrial stem cell markers notch-1 and numb are associated with endometriosis. Reprod Biomed Online 36:294–301. https://doi.org/10.1016/j.rbmo.2017.11.010 Götte M, Wolf M, Staebler A, Buchweitz O, Kelsch R, Schüring AN, Kiesel L (2008) Increased expression of the adult stem cell marker Musashi-1 in endometriosis and endometrial carcinoma. J Pathol 215:317–329. https://doi.org/10.1002/path.2364 Noyes RW, Hertig AT, Rock J (2019) Reprint of: dating the endometrial biopsy. Fertil Steril 112:e93–e115. https://doi.org/10.1016/j.fertnstert.2019.08.079 Reis FM, Santulli P, Marcellin L, Borghese B, Lafay-Pillet MC, Chapron C (2020) Superficial peritoneal endometriosis: clinical characteristics of 203 confirmed cases and 1292 endometriosis-free controls. Reprod Sci 27:309–315. https://doi.org/10.1007/s43032-019-00028-1 Cruz CD, Del Puerto HL, Rocha AL, Cavallo IK, Clarizia AD, Petraglia F, Reis FM (2015) Expression of Nodal, Cripto, SMAD3, phosphorylated SMAD3, and SMAD4 in the proliferative endometrium of women with endometriosis. Reprod Sci 22:527–533. https://doi.org/10.1177/1933719114549855 Fuhrich DG, Lessey BA, Savaris RF (2013) Comparison of HSCORE assessment of endometrial beta3 integrin subunit expression with digital HSCORE using computerized image analysis (ImageJ). Anal Quant Cytopathol Histopathol 35:210–216 Gargett CE, Schwab KE, Zillwood RM, Nguyen HP, Wu D (2009) Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod 80:1136–1145. https://doi.org/10.1095/biolreprod.108.075226 Sbracia M, Scarpellini F, Marconi D, Zupi E, Klinger F, Arduini D (2007) Stem cell antigens in ectopic epithelial cells of endometriotic lesions: is endometriosis a disease originated from stem cells? Fertil Steril 88:S61–S61. https://doi.org/10.1016/j.fertnstert.2007.07.209 Lammie A, Drobnjak M, Gerald W, Saad A, Cote R, Cordon-Cardo C (1994) Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem 42:1417–1425. https://doi.org/10.1177/42.11.7523489 Elmore LW, Domson K, Moore JR, Kornstein M, Burks RT (2001) Expression of c-kit (CD117) in benign and malignant human endometrial epithelium. Arch Pathol Lab Med 125:146–151. https://doi.org/10.1043/0003-9985(2001)125%3c0146:eockci%3e2.0.co;2 Osuga Y et al (2000) Stem cell factor (SCF) concentrations in peritoneal fluid of women with or without endometriosis. Am J Reprod Immunol (New York, NY: 1989) 44:231–235. https://doi.org/10.1111/j.8755-8920.2000.440407.x Uzan C, Cortez A, Dufournet C, Fauvet R, Siffroi JP, Darai E (2005) Endometrium from women with and without endometriosis, and peritoneal, ovarian and bowel endometriosis, show different c-kit protein expression. J Reprod Immunol 65:55–63. https://doi.org/10.1016/j.jri.2004.09.002 Pacchiarotti A, Caserta D, Sbracia M, Moscarini M (2011) Expression of oct-4 and c-kit antigens in endometriosis. Fertil Steril 95:1171–1173. https://doi.org/10.1016/j.fertnstert.2010.10.029 Chan RW, Schwab KE, Gargett CE (2004) Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod 70:1738–1750. https://doi.org/10.1095/biolreprod.103.024109 Funding Research supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Author information Authors and Affiliations Contributions Conceived the study: FMR, AFC; included samples: MMC, IdA, MSA; performed laboratory tests: FRO, MC, CDC, HLDP; documented and interpreted results: FRO, MC, CDC, HLDP; drafted manuscript: FRO, MC; edited manuscript: FMR, MSA, AFC. Corresponding author Ethics declarations Conflict of interest No potential conflict of interest was reported by the authors. Ethical approval The study was approved by the Research Ethics Committee at Federal University of Minas Gerais under protocol number ETIC/0628.0.203.000-09. Consent to participate Since the study was retrospective and used archived samples with numeric codes, it was exempted from obtaining participant’s consent. Consent to publication Does not apply. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions About this article Cite this article Oliveira, F.R., Casalechi, M., Carneiro, M.M. et al. Immunolocalization of stem/progenitor cell biomarkers Oct-4, C-kit and Musashi-1 in endometriotic lesions. Mol Biol Rep 48, 6863–6870 (2021). https://doi.org/10.1007/s11033-021-06685-3 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s11033-021-06685-3