{"paper_id":"6ce2e273-468e-4649-bd3f-3bff209a2a50","body_text":"Abstract\nPluripotent, very small embryonic-like stem cells (VSELs) and tissue-committed ‘progenitors’ termed endometrial stem cells (EnSCs) are reported in mouse uterus. They express gonadal and gonadotropin hormone receptors and thus are vulnerable to early-life endocrine insults. Neonatal exposure of mouse pups to endocrine disruption cause stem/progenitor cells to undergo epigenetic changes, excessive self-renewal, and blocked differentiation that results in various uteropathies including non-receptive endometrium, hyperplasia, endometriosis, adenomyosis, and cancer-like changes in adult life. Present study investigated reversal of these uteropathies, by normalizing functions of VSELs and EnSCs. Two strategies were evaluated including (i) transplanting mesenchymal stromal cells (provide paracrine support) on D60 or (ii) oral administration of XAR (epigenetic regulator) daily from days 60–100 and effects were studied later in 100 days old mice. Results show normalization of stem/progenitor cells (Oct-4, Oct-4A, Sox-2, Nanog) and Wnt signalling (Wnt-4, β-catenin, Axin-2) specific transcripts. Flow cytometry results showed reduced numbers of 2–6 µm, LIN-CD45-SCA-1 + VSELs. Hyperplasia (Ki67) of epithelial (Pax-8, Foxa-2) and myometrial (α-Sma, Tgf-β) cells was reduced, adenogenesis (differentiation of glands) was restored, endometrial receptivity and differentiation (LIF, c-KIT, SOX-9, NUMB) and stromal cells niche (CD90, VIMENTIN, Pdgfra, Vimentin) were improved, cancer stem cells markers (OCT-4, CD166) were reduced while tumor suppressor genes (PTEN, P53) and epigenetic regulators (Ezh-2, Sirt-1) were increased. To conclude, normalizing VSELs/EnSCs to manage uteropathies provides a novel basis for initiating clinical studies. The study falls under the umbrella of United Nations Sustainable Development Goal 3 to ensure healthy lives and well-being for all of all ages.\nGraphical Abstract\nData Availability\nAll relevant data is included in the manuscript and the supplement.\nCode Availability\nNot applicable.\nAbbreviations\n- VSELs :\n-\nVery Small embryonic-like stem cells\n- EnSCs :\n-\nEndometrial stem progenitor cells\n- MSC :\n-\nMesenchymal stem/stromal cell\n- DES :\n-\nDiethylstilbesterol\n- E2 :\n-\nEstradiol\n- EDCs :\n-\nEndocrine disrupting chemicals\n- PND :\n-\nPostnatal day\n- OCT-4 :\n-\nOctamer-binding transcription factor 4\n- SOX-2 :\n-\nSex determining region Y-box 2\n- NANOG :\n-\nHomeobox transcription factor\n- SCA-1 :\n-\nStem cells antigen-1\n- SSEA-1 :\n-\nStage-specific embryonic antigen-1\n- LIF :\n-\nLeukemia inhibitory factor\n- c-KIT :\n-\nReceptor tyrosine kinase\n- CSCs :\n-\nCancer stem cells\n- CD166 (ALCAM) :\n-\nActivated leukocyte cell adhesion molecule\n- GFP :\n-\nGreen fluorescent protein\n- α-SMA :\n-\nAlpha-smooth muscle actin\n- 7AAD :\n-\n7-Amino-actinomycin D\n- PAX-8 :\n-\nPaired-box gene 8\n- FOXA-2 :\n-\nForkhead box protein A2\n- NUMB :\n-\nNUMB: endocytic adaptor protein\n- CD90 :\n-\nCluster of Differentiation 90\n- Ki-67 :\n-\nMarker of proliferation\n- PTEN :\n-\nPhosphatase and TENsin homolog deleted on chromosome10\n- P53 :\n-\nTumour suppressor protein p53\n- SIRT-1 :\n-\nSilent mating type information regulation 2 homolog-1\n- DNMTs :\n-\nDNA methyltransferases\nReferences\nSkakkebæk, N. 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Human-derived model systems in gynecological cancer research. Trends in Cancer, 6, 1031–1043. https://doi.org/10.1016/j.trecan.2020.07.007\nAcknowledgements\nHelp from Confocal Microscopy; Flow Cytometry and Histology Central Facilities at NIRRCH is acknowledged. Subhan MD help is acknowledged for XAR treatment. We acknowledge all those who have published data that may be directly relevant but may not have been quoted.\nFunding\nThe study was supported by the core support provided by Indian Council of Medical Research, Government of India, New Delhi. PS acknowledges the DST-INSPIRE fellowship (IF170144).\nAuthor information\nAuthors and Affiliations\nContributions\nDB planned the study, arrange the funds, and helped in manuscript drafting. All authors discussed the findings, read, and approved the final version. PS helped design the study, performed all experiments, and wrote the article. SMM performed all the surgeries. AT provided XAR- a nano-formulation of Resveratrol.\nCorresponding author\nEthics declarations\nEthics Approval\nProject no-16/17 was approved on 21 December 2017.\nConsent to Participate\nNot applicable.\nConsent for Publication\nNIRRCH manuscript number RA/1420/12-2022.\nConflict of Interest\nAuthors declare no conflict of interest whatsoever that could be perceived as prejudicing the impartiality of the research reported. This study was completed when DB was at NIRRCH and no conflict of interest existed with Epigeneres Biotech Pvt Ltd., Mumbai which she joined after superannuation. XAR was provided as a gift by Epigeneres as an outcome of an earlier collaborative publication (https://doi.org/10.1007/s12015-017-9784-7).\nAdditional information\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nAll work is done at NIRRCH.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\nESM 1 (download DOCX )\n(DOCX 3.29 MB)\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nSingh, P., Metkari, S.M., Tripathi, A. et al. Reversing Uteropathies Including Cancer-Like Changes in Mice by Transplanting Mesenchymal Stromal Cells or XAR Treatment. Stem Cell Rev and Rep 20, 258–282 (2024). https://doi.org/10.1007/s12015-023-10632-z\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s12015-023-10632-z","source_license":"public-domain-us","license_restricted":false}