{"paper_id":"1fc1dbd2-dd6a-4ce7-af4b-5a5a7336a9ac","body_text":"Abstract\nBackground\nHuman endometrial stromal cells (hEnSCs) are central to female fertility. This study investigated the cellular and molecular landscape of hEnSCs and identified inter-individual variations that may influence reproductive potential.\nMethods and results\nEndometrial biopsies were obtained from 16 women undergoing gynecologic evaluation. Primary hEnSCs were isolated, expanded, and characterized for mesenchymal stem cell properties. Stemness, receptivity, and decidualization capacity were assessed using RT-qPCR and RNA sequencing, followed by differential gene expression and pathway enrichment analyses. Integrated cellular and transcriptomic analyses revealed donor-dependent molecular heterogeneity. Key genes involved in stemness (OCT4, KLF4, MYC), decidualization (PRL, IGFBP1), and endometrial receptivity (ESR1, PGR, HOXA10, and HOXA11) showed significant variability among individuals. RNA-seq analyses further identified differentially expressed genes associated with clinical variables, including age, body mass index (BMI), and endometrial thickness. Age-related transcriptomic changes included enrichment of genes involved in extracellular matrix organization, cell adhesion, and immune regulation. A higher BMI was connected to altered regulation of genes related to the cell cycle, extracellular matrix, and signaling receptor regulatory activity, while a thin endometrium was associated with downregulation of genes involved in cell-cell junction, signaling receptor regulatory activity, and epidermal development.\nConclusion\nhEnSCs exhibit significant individual-dependent molecular heterogeneity, with donor-specific variations influencing crucial biological pathways related to receptivity, stemness, and decidualization. These molecular profiles, influenced by age, BMI, and endometrial thickness, may reflect the fertility potential of the endometrium. Recognition of such intrinsic, individual-specific endometrial variation emphasizes the importance of personalized approaches in fertility assessment and reproductive treatments.\nSimilar content being viewed by others\nData availability\nData will be made available to the editors of the journal for review or query upon request to the corresponding author.\nAbbreviations\n- OCT4:\n-\nPOU class 5 homeobox 1(POU5F1)\n- KLF4:\n-\nKruppel like factor 4\n- SOX2:\n-\nSRY-box transcription factor 2\n- MYC:\n-\nMYC proto-oncogene, bHLH transcription factor\n- ESR 1:\n-\nEstrogen receptor 1\n- PGR:\n-\nProgesterone receptor\n- HOXA10:\n-\nHomeobox A10\n- HOXA11:\n-\nHomeobox A11\n- PRL:\n-\nProlactin\n- IGFBP1:\n-\nInsulin-like growth factor binding protein 1\n- LEP:\n-\nLeptin\n- FABP4:\n-\nFatty Acid Binding Protein 4\n- COL1A1:\n-\nCollagen Type I Alpha 1\n- SPARC:\n-\nOsteonectin\n- ACAN:\n-\nAggrecan\n- COL2A1:\n-\nCollagen Type II Alpha 1\n- GAPDH:\n-\nGlyceraldehyde-3-phosphate dehydrogenase\n- LIF:\n-\nLeukemia inhibitory factor\n- MMP7:\n-\nMatrix metallopeptidase 7\n- MUC1:\n-\nMucin 1, cell surface associated\n- ITGAV:\n-\nIntegrin subunit alpha V\n- ANXA2:\n-\nAnnexin A2\n- IL15:\n-\nInterleukin 15\n- IGF1R:\n-\nInsulin-like growth factor 1 receptor\n- BMP2:\n-\nBone morphogenetic protein 2\n- DKK1:\n-\nDickkopf WNT signaling pathway inhibitor 1\n- ITGA4:\n-\nIntegrin subunit alpha 4\n- DCN:\n-\nDecorin\n- HAND2:\n-\nHeart and neural crest derivatives expressed 2\n- ELN:\n-\nElastin\n- TIMP3:\n-\nTIMP metallopeptidase inhibitor 3\n- BMI1:\n-\nBMI1 proto-oncogene, polycomb ring finger\n- SALL4:\n-\nSpalt like transcription factor 4\n- KLF2:\n-\nKruppel-like factor 2\n- PPIA:\n-\nPeptidylprolyl isomerase A (Cyclophilin A)\n- ALDH1A1:\n-\nAldehyde dehydrogenase 1 family member A1\n- SOX15:\n-\nSRY-box transcription factor 15\n- NOTCH1:\n-\nNotch receptor 1\n- SLC34A2:\n-\nSolute carrier family 34 member 2\n- HOXB9:\n-\nHomeobox B9\n- HSH2D:\n-\nHematopoietic SH2 domain containing\n- RASSF6:\n-\nRas association domain family member 6\n- DOC2B:\n-\nDouble C2 domain beta\n- NMUR2:\n-\nNeuromedin U receptor 2\n- VAV1:\n-\nVav guanine nucleotide exchange factor 1\n- MUC5AC:\n-\nMucin 5AC, oligomeric mucus/gel-forming\n- PLVAP:\n-\nPlasmalemma vesicle associated protein\n- TDRD15:\n-\nTudor domain containing 15\n- CX3CL1:\n-\nC-X3-C motif chemokine ligand 1 (Fractalkine)\n- CNTNAP2:\n-\nContactin associated protein-like 2\n- SERPINA1:\n-\nSerpin family A member 1 (Alpha-1-antitrypsin)\n- LCN2:\n-\nLipocalin 2\n- MDFI:\n-\nMyoD family inhibitor\n- COL22A1:\n-\nCollagen type XXII alpha 1 chain\n- TDRD15:\n-\nTudor domain containing 15\n- SLA:\n-\nSrc-like adaptor\n- TNFSF18:\n-\nTumor necrosis factor superfamily member 18 (GITRL)\n- ACTG2:\n-\nActin gamma 2, smooth muscle\n- NKX3-2:\n-\nNK3 homeobox 2\n- CCDC144A:\n-\nCoiled-coil domain containing 144 A\n- EPYC:\n-\nEpiphycan\n- PLXDC1:\n-\nPlexin domain containing 1\n- C11orf87:\n-\nChromosome 11 open reading frame 87\n- GRM4:\n-\nGlutamate metabotropic receptor 4\n- SPHKAP:\n-\nSphingosine kinase type 1 interacting protein\n- NKX2-6:\n-\nNK2 homeobox 6\n- LCE2A:\n-\nLate cornified envelope 2 A\n- HDC:\n-\nHistidine decarboxylase\n- LYPD6B:\n-\nLY6/PLAUR domain containing 6B\n- SBSN:\n-\nSuprabasin\n- PLAC8:\n-\nPlacenta-specific 8\n- MGAM:\n-\nMaltase-glucoamylase\n- PTPRQ:\n-\nProtein tyrosine phosphatase receptor type Q\n- MAB21L1:\n-\nMab-21 like 1\n- GLDN:\n-\nGliomedin\n- ABI3:\n-\nABI family member 3 (Abl interactor 3)\n- DMRTA2:\n-\nDMRT like family A2\n- EPHA3:\n-\nEPH receptor A3\n- HLA-DPA1:\n-\nMajor histocompatibility complex, class II, DP alpha 1\n- HLA-DQB1:\n-\nMajor histocompatibility complex, class II, DP beta 1\n- PWP2:\n-\nPeriodic tryptophan protein 2 homolog\n- VIT:\n-\nVitrin\n- TMEM100:\n-\nTransmembrane protein 100\n- GPRIN2:\n-\nG protein regulated inducer of neurite outgrowth 2\n- PRODH:\n-\nProline dehydrogenase 1\n- UGT1A6:\n-\nUDP glucuronosyltransferase family 1 member A6\n- CASC19:\n-\nCancer susceptibility 19 (long non-coding RNA)\n- ADAMTSL3:\n-\nADAMTS like 3\n- LINC01411:\n-\nLong intergenic non-protein coding RNA 1411\n- SLC52A3:\n-\nSolute carrier family 52 member 3 (riboflavin transporter 3)\n- NOS1:\n-\nNitric oxide synthase 1\n- CA2:\n-\nCarbonic anhydrase 2\nReferences\nZorrilla M, Yatsenko AN (2013) The genetics of infertility: current status of the field. 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FASEB J. https://doi.org/10.1096/fj.202101579R\nFunding\nThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science and ICT (MSIT) of the Government of South Korea (Grant Number: RS-2024-00405287) and grant funded by the Institute of Planning and Evaluation for Technology (IPET) through Ministry of Agriculture, Food and Rural Affairs (MAFRA) (grant number: 321025-05).\nAuthor information\nAuthors and Affiliations\nContributions\nConcept/design: U.R., E.Y.K, D.C.M.K., Y.B.K., and M.K.K.Sample collection: U.R., E.Y.K, R.E.K., J.W.H., and Y.J.K.Experiments: U.R., E.Y.K., D.C.M.K., R.E.K., J.W.HData analysis: U.R., and D.C.M.KBioinformatics: U.R., and D.C.M.KManuscript drafting: U.R., E.Y.K., D.C.M.K., and M.K.K.Manuscript revision: U.R., E.Y.K., D.C.M.K., R.E.K., J.W.H., Y.J.K., Y.B.K., and M.K.K.Supervision: M.K.K.Funding acquisition: M.K.K.\nCorresponding author\nEthics declarations\nCompeting interests\nThe authors declare no competing interests.\nEthics approval\nThis study was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Chungnam National University Hospital (IRB no. CNUH 2022-11-002).\nConsent to participate\nInformed consent was obtained from all individual participants included in the study.\nConsent to publish\nNot applicable.\nAdditional information\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\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\nRanaraja, U., Kim, E.Y., Kulatunga, D.C. . et al. Individual-dependent molecular heterogeneity in human endometrial stromal cells: a potential determinant of female fertility. Mol Biol Rep 53, 492 (2026). https://doi.org/10.1007/s11033-026-11670-9\nReceived:\nAccepted:\nPublished:\nVersion of record:\nDOI: https://doi.org/10.1007/s11033-026-11670-9","source_license":"CC0","license_restricted":false}