Pain pathways and stem cells in endometriosis pathogenesis

As a gynecological disease, endometriosis is a disease in which pain and inflammation are important parts. Endometriosis is a chronic, estrogen-related situation with a multifactorial etiology that remains incompletely understood. Endometriosis affects approximately 6–10% of females and is a prominent reason of infertility. Despite being histologically benign, endometriosis displays invasive behaviors and is associated with systemic inflammatory responses and immune dysfunction. In this text, endometriosis pathogenesis and pain associated with endometriosis is comprehensively explored with particular emphasis on inflammation, pain mechanisms and the emerging role of stem cells. Several theories, including coelomic metaplasia, lymphovascular dissemination, retrograde menstruation, and embryonic rest theory have been recommended to clarify the ectopic location of endometrial tissue. Among these, the immune-mediated inflammatory microenvironment and aberrant neurogenesis are considered in disease progression and the development of pain. The multifactorial nature of endometriosis-associated pain—encompassing inflammatory, neuropathic, and oxidative stress-related mechanisms—highlights the limitations of hormonal treatments and the necessity for new therapeutic perspectives. In this respect, the involvement of stem cells, particularly endometrial and mesenchymal stem cells, has attracted growing interest. These cells are implicated not only in the pathophysiology of the disease but also show promise in regenerative and immunomodulatory therapies. This review aims to present an integrative perspective on endometriosis by examining recent evidence on inflammatory signaling, neuroimmune alterations, and stem cell biology. A deeper understanding of these mechanisms may open new avenues for personalized and multidisciplinary treatment strategies in endometriosis management. Similar content being viewed by others Data availability No datasets were generated or analysed during the current study. Abbreviations - NK: - Natural Killer - MUC5B: - Mucin 5B - NRG1: - Neuregulin 1 - ERBB3: - Erb-B2 Receptor Tyrosine Kinase 3 - IL: - Interleukin - PG: - Prostaglandin - NGF: - Nerve Growth Factor - TNF-α: - Tumor Necrosis Factor-Alpha - ROS: - Reactive Oxygen Species - miR: - MicroRNA - CD: - Cluster of Differentiation - LGR5: - Leucine Rich Repeat Containing G-Protein Coupled Receptor 5 - NKT: - Natural Killer T - SELL: - Selectin L - PDGF-Rβ: - Platelet Derived Growth Factor-Receptor Beta - ITGAX: - Integrin Subunit Alpha X - FGFBP2: - Fibroblast Growth Factor Binding Protein 2 - FCGR3A: - Fc Gamma Receptor IIIa - DIE: - Deep Infiltrating Endometriosis - KIR: - Killer Cell Immunoglobulin Like Receptor - NT: - Neurotrophin - BDNF: - Brain-Derived Neurotrophic Factor - Lct: - Lactase - TSG-6: - Tumor Necrosis Factor-Stimulated Gene-6 - LDL: - Low Density Lipoprotein - PTGES3: - Prostaglandin E Synthase 3 - NF-κβ: - Nuclear Factor Kappa Beta - ATP: - Adenosine Triphosphate - ADP: - Adenosine Diphosphate - P2X3: - P2X Ligand-Gated Ion Channel 3 - ADA: - Adenosine Deaminase - ENPP1: - Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 - NSAID: - Non-Steroidal Anti-Inflammatory Drugs - H + BSO: - Hysterectomy with a Bilateral Salpingo-Oophorectomy - SC: - Stem Cell - PSC: - Pluripotent Stem Cell - MSC: - Mesenchymal Stem Cell - BMSC: - Bone Marrow-Derived Mesenchymal Stem Cell - ASC: - Adipose Tissue-Derived Stem Cell - VEGF-A: - Vascular Endothelial Growth Factor-A - NAC: - N-acetylcysteine - HGF-1: - Hepatocyte Growth Factor-1 - HLA: - Human Leukocyte Antigen - hEDSC: - Human Endometrial-Derived Stem Cell - ESC: - Endometrial Stem Cell - eMSC: - Endometrial Mesenchymal Stem Cell - SP: - Side Population - MenSC: - Menstrual Stem Cell - MCP-1: - Monocyte Chemoattractant Protein-1 - MCAM: - Melanoma Cell Adhesion Molecule - SSEA-1: - Stage-Specific Embryonic Antigen-1 - DNA: - Deoxyribonucleic Acid - eMSC: - Endometrial Mesenchymal Stem Cell - SUSD2: - Sushi Domain Containing-2 - CXCL8: - C-X-C-Motif Chemokine Ligand 8 - TGF-β1: - Transforming Growth Factor-Beta 1 - ICAM-1: - Intercellular Adhesion Molecule-1 - SALL4: - Spalt Like Transcription Factor 4 - LT: - Leukotriene - SOX2: - SRY-Box Transcription Factor 2 - TX: - Thromboxane - IFN-γ: - Interferon Gamma - ABCG2: - ATP-Binding Cassette Transporter G2. SF-1:Steroidogenic Factor 1 - HOXA10: - Homeobox A10 - EMT: - Epithelial-Mesenchymal Transition - MAPK: - Mitogen-Activated Protein Kinase - APC: - Antigen-Presenting Cell - TNF-β: - Tumor Necrosis Factor-Beta - GM-CSF: - Granulocyte-Macrophage Colony-Stimulating Factor - CGRP: - Calcitonin Gene-Related Peptide - MC: - Mast Cell - KIR2DL1: - Killer Cell Immunoglobulin Like Receptor, Two Ig Domains And Long Cytoplasmic Tail 1 - MMP: - Matrix Metalloproteinase - COX-2: - Cyclooxygenase-2

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Biomedicines. https://doi.org/10.3390/biomedicines11010039 Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author information Authors and Affiliations Contributions Author ContributionsAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [H.A.]. Evaluation of the manuscript, detailed examination and supervision were performed by [H.E.]. The first draft of the manuscript was written by [H.A.] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Corresponding author Ethics declarations Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer 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. About this article Cite this article Aydin, H., Elbe, H. Pain pathways and stem cells in endometriosis pathogenesis. Mol Biol Rep 52, 860 (2025). https://doi.org/10.1007/s11033-025-10973-7 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s11033-025-10973-7