Endometriosis stromal cells induce bone marrow mesenchymal stem cell differentiation and PD-1 expression through paracrine signaling

Endometriosis is an estrogen-dependent, inflammatory gynecological disorder characterized by the growth of endometrial cells in lesions outside the uterus. Bone marrow-derived cells (BMDCs) engraft lesions and increase lesion size. Do endometriosis cells regulate differentiation of engrafted BMDCs in the pathogenesis and growth of endometriosis? Here, we report endometriosis derived stromal cells promote the differentiation of BMDCs to stromal, epithelial and leukocyte cell fates through paracrine signaling. In-vitro studies demonstrated that both mRNA and protein levels of vimentin, cytokeratin and PD-1 were significantly increased in BMDCs cocultured with stromal cells from endometriosis (ENDO) patients compared to stromal cells from normal endometrium (CNTL). Increased expression of PD-1 has been reported in malignancy where it promotes T cell quiescence and immune tolerance. Increased PD-1 was also confirmed in-vivo where we showed that PD-1 expression was induced in BMDCs engrafted into endometriotic lesions in a murine model of endometriosis. AMD3100, an antagonist for CXCR4 receptor inhibited PD-1 expression in BMDCs suggesting that PD-1 induction requires CXCL12. These results suggest that endometriosis stimulated BMDC differentiation through paracrine signaling and increased T cell PD-1 expression. Increased PD-1 expression may be one mechanism by which endometriosis avoids immune surveillance. Similar content being viewed by others

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We thank Aya Tal for anti-CD3 staining and Marie Gaye for proofreading the manuscript. Funding This work was supported by the Endometriosis Foundation of America AWD0003567. Author information Authors and Affiliations Contributions PC performed experiments, analyzed the data and drafted the manuscript. RM designed the study, study implementation, analyzed the data, prepared the figures, drafted and revised the manuscript. SH participated in the experiments and read the manuscript. HT conceived, design study, analyzed the data and finalized the manuscript. Corresponding author Ethics declarations Conflict of interest The authors declare that they have no conflict of interest. Consent for publication All authors have read the manuscript and authorized the submission for publication. Ethical approval All procedures performed in this study involving patients and animals were in accordance with the ethical standards of the Ethical Committee of Yale University. Appropriate guidelines have been followed for the use of animals. Written informed consent was signed by all patients. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic supplementary material Below is the link to the electronic supplementary material. Suppl Fig. 1 (download PDF ) Immunostaining of lesions showing T-cells. Representative image of lesion section showing CD3 expression, a marker for T-cells. Murine lesions were stained with anti-CD3 antibody (brown). Scale bar: 100 μm. (PDF 713 kb) Suppl. Fig. 2 (download TIF ) Gross morphology of endometriotic lesions: Circles (yellow) indicate endometriotic lesions (left). H & E staining of lesion tissue section showing glandular uterine structure (right). (TIF 630 kb) Rights and permissions About this article Cite this article Chen, P., Mamillapalli, R., Habata, S. et al. Endometriosis stromal cells induce bone marrow mesenchymal stem cell differentiation and PD-1 expression through paracrine signaling. Mol Cell Biochem 476, 1717–1727 (2021). https://doi.org/10.1007/s11010-020-04012-1 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s11010-020-04012-1