Skip to main content
SpringerLink
Log in

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

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Giudice LC (2010) Clinical practice. Endometriosis N Engl J Med 362:2389–2398. https://doi.org/10.1056/NEJMcp1000274

    Article  CAS  PubMed  Google Scholar 

  2. Johnson NP, Hummelshoj L (2013) Consensus on current management of endometriosis. Hum Reprod 28:1552–1568. https://doi.org/10.1093/humrep/det050

    Article  PubMed  Google Scholar 

  3. Mounsey AL, Wilgus A, Slawson DC (2006) Diagnosis and management of endometriosis. Am Fam Physician 74:594–600

    PubMed  Google Scholar 

  4. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM (1984) Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol 64:151–154

    CAS  PubMed  Google Scholar 

  5. Tal A, Tal R, Pluchino N, Taylor HS (2019) Endometrial cells contribute to preexisting endometriosis lesions in a mouse model of retrograde menstruationdagger. Biol Reprod 100:1453–1460. https://doi.org/10.1093/biolre/ioz039

    Article  PubMed  PubMed Central  Google Scholar 

  6. Polymeri A, Giannobile WV, Kaigler D (2016) Bone marrow stromal stem cells in tissue engineering and regenerative medicine. Horm Metab Res 48:700–713. https://doi.org/10.1055/s-0042-118458

    Article  CAS  PubMed  Google Scholar 

  7. Pluchino N, Taylor HS (2016) Endometriosis and stem cell trafficking. Reprod Sci 23:1616–1619. https://doi.org/10.1177/1933719116671219

    Article  CAS  PubMed  Google Scholar 

  8. Sakr S, Naqvi H, Komm B, Taylor HS (2014) Endometriosis impairs bone marrow-derived stem cell recruitment to the uterus Whereas Bazedoxifene treatment leads to endometriosis regression and improved uterine stem cell engraftment. Endocrinology 155:1489–1497. https://doi.org/10.1210/en.2013-1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Quarto R, Mastrogiacomo M, Cancedda R, Kutepov SM, Mukhachev V, Lavroukov A, Kon E, Marcacci M (2001) Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 344:385–386. https://doi.org/10.1056/nejm200102013440516

    Article  CAS  PubMed  Google Scholar 

  10. Ishida T, Inaba M, Hisha H, Sugiura K, Adachi Y, Nagata N, Ogawa R, Good RA, Ikehara S (1994) Requirement of donor-derived stromal cells in the bone marrow for successful allogeneic bone marrow transplantation. Complete prevention of recurrence of autoimmune diseases in MRL/MP-Ipr/Ipr mice by transplantation of bone marrow plus bones (stromal cells) from the same donor. J Immunol 152:3119–3127

    CAS  PubMed  Google Scholar 

  11. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441. https://doi.org/10.1016/s0140-6736(04)16104-7

    Article  PubMed  Google Scholar 

  12. Ikehara S (2001) Successful allogeneic bone marrow transplantation. Crucial roles of stromal cells in prevention of graft rejection. Acta Haematol 105:172–178. https://doi.org/10.1159/000046561

    Article  CAS  PubMed  Google Scholar 

  13. Herington JL, Bruner-Tran KL, Lucas JA, Osteen KG (2011) Immune interactions in endometriosis. Expert Rev Clin Immunol 7:611–626. https://doi.org/10.1586/eci.11.53

    Article  PubMed  PubMed Central  Google Scholar 

  14. Agostinis C, Zorzet S, De Leo R, Zauli G, De Seta F, Bulla R (2015) The combination of N-acetyl cysteine, alpha-lipoic acid, and bromelain shows high anti-inflammatory properties in novel in vivo and in vitro models of endometriosis. Mediators Inflamm 2015:918089. https://doi.org/10.1155/2015/918089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, Agarwal A (2002) Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 17:426–431. https://doi.org/10.1093/humrep/17.2.426

    Article  CAS  PubMed  Google Scholar 

  16. Chen D, Tang P, Liu L, Wang F, Xing H, Sun L, Jiang Z (2018) Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway. Cell Cycle 17:858–867. https://doi.org/10.1080/15384101.2018.1442624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Walankiewicz M, Grywalska E, Polak G, Korona-Glowniak I, Witt E, Surdacka A, Kotarski J, Rolinski J (2018) The increase of circulating PD-1- and PD-L1-expressing lymphocytes in endometriosis: correlation with clinical and laboratory parameters. Mediators Inflamm 2018:7041342. https://doi.org/10.1155/2018/7041342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sharpe AH, Pauken KE (2018) The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 18:153–167. https://doi.org/10.1038/nri.2017.108

    Article  CAS  PubMed  Google Scholar 

  19. Chen X, Fosco D, Kline DE, Meng L, Nishi S, Savage PA, Kline J (2014) PD-1 regulates extrathymic regulatory T-cell differentiation. Eur J Immunol 44:2603–2616. https://doi.org/10.1002/eji.201344423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lim TS, Chew V, Sieow JL, Goh S, Yeong JP, Soon AL, Ricciardi-Castagnoli P (2016) PD-1 expression on dendritic cells suppresses CD8(+) T cell function and antitumor immunity. Oncoimmunology 5:e1085146. https://doi.org/10.1080/2162402x.2015.1085146

    Article  PubMed  Google Scholar 

  21. McKay JT, Egan RP, Yammani RD, Chen L, Shin T, Yagita H, Haas KM (2015) PD-1 suppresses protective immunity to Streptococcus pneumoniae through a B cell-intrinsic mechanism. J Immunol 194:2289–2299. https://doi.org/10.4049/jimmunol.1401673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu L, Lv C, Su Y, Li C, Zhang H, Zhao X, Li M (2019) Expression of programmed death-1 (PD-1) and its ligand PD-L1 is upregulated in endometriosis and promoted by 17beta-estradiol. Gynecol Endocrinol 35:251–256. https://doi.org/10.1080/09513590.2018.1519787

    Article  CAS  PubMed  Google Scholar 

  23. (1997) Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 67:817–21. https://doi.org/10.1016/s0015-0282(97)81391-x

  24. Ryan IP, Schriock ED, Taylor RN (1994) Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab 78:642–649. https://doi.org/10.1210/jcem.78.3.8126136

    Article  CAS  PubMed  Google Scholar 

  25. Noble LS, Takayama K, Zeitoun KM, Putman JM, Johns DA, Hinshelwood MM, Agarwal VR, Zhao Y, Carr BR, Bulun SE (1997) Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab 82:600–606. https://doi.org/10.1210/jcem.82.2.3783

    Article  CAS  PubMed  Google Scholar 

  26. Krikun G, Mor G, Alvero A, Guller S, Schatz F, Sapi E, Rahman M, Caze R, Qumsiyeh M, Lockwood CJ (2004) A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology 145:2291–2296. https://doi.org/10.1210/en.2003-1606

    Article  CAS  PubMed  Google Scholar 

  27. Barr A, Manning D (1999) G proteins techniques of analysis. CRC Press Inc, Boca Raton, pp 227–245

    Google Scholar 

  28. Tal R, Liu Y, Pluchino N, Shaikh S, Mamillapalli R, Taylor HS (2016) A murine 5-fluorouracil-based submyeloablation model for the study of bone marrow-derived cell trafficking in reproduction. Endocrinology 157:3749–3759. https://doi.org/10.1210/en.2016-1418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Du H, Taylor HS (2007) Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells 25:2082–2086. https://doi.org/10.1634/stemcells.2006-0828

    Article  CAS  PubMed  Google Scholar 

  30. Lee B, Du H, Taylor HS (2009) Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod 80:79–85. https://doi.org/10.1095/biolreprod.108.070391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang X, Mamillapalli R, Mutlu L, Du H, Taylor HS (2015) Chemoattraction of bone marrow-derived stem cells towards human endometrial stromal cells is mediated by estradiol regulated CXCL12 and CXCR4 expression. Stem Cell Res 15:14–22. https://doi.org/10.1016/j.scr.2015.04.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang WB, Cheng MJ, Huang YT, Jiang W, Cong Q, Zheng YF, Xu CJ (2012) A study in vitro on differentiation of bone marrow mesenchymal stem cells into endometrial epithelial cells in mice. Eur J Obstet Gynecol Reprod Biol 160:185–190. https://doi.org/10.1016/j.ejogrb.2011.10.012

    Article  CAS  PubMed  Google Scholar 

  33. Morelli SS, Rameshwar P, Goldsmith LT (2013) Experimental evidence for bone marrow as a source of nonhematopoietic endometrial stromal and epithelial compartment cells in a murine model. Biol Reprod 89:7. https://doi.org/10.1095/biolreprod.113.107987

    Article  CAS  PubMed  Google Scholar 

  34. Yin M, Zhou HJ, Lin C, Long L, Yang X, Zhang H, Taylor H, Min W (2019) CD34(+)KLF4(+) stromal stem cells contribute to endometrial regeneration and repair. Cell Rep 27:2709-2724.e3. https://doi.org/10.1016/j.celrep.2019.04.088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Moridi I, Mamillapalli R, Cosar E, Ersoy GS, Taylor HS (2016) Bone marrow stem cell chemotactic activity is induced by elevated CXCl12 in endometriosis. Reprod Sci. https://doi.org/10.1177/1933719116672587

    Article  PubMed  PubMed Central  Google Scholar 

  36. Pluchino N, Mamillapalli R, Shaikh S, Habata S, Tal A, Gaye M, Taylor HS (2020) CXCR4 or CXCR7 antagonists treat endometriosis by reducing bone marrow cell trafficking. J Cell Mol Med 24:2464–2474. https://doi.org/10.1111/jcmm.14933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Du H, Naqvi H, Taylor HS (2012) Ischemia/reperfusion injury promotes and granulocyte-colony stimulating factor inhibits migration of bone marrow-derived stem cells to endometrium. Stem Cells Dev 21:3324–3331. https://doi.org/10.1089/scd.2011.0193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tal R, Shaikh S, Pallavi P, Tal A, Lopez-Giraldez F, Lyu F, Fang YY, Chinchanikar S, Liu Y, Kliman HJ, Alderman M 3rd, Pluchino N, Kayani J, Mamillapalli R, Krause DS, Taylor HS (2019) Adult bone marrow progenitors become decidual cells and contribute to embryo implantation and pregnancy. PLoS Biol 17:e3000421. https://doi.org/10.1371/journal.pbio.3000421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Taylor HS (2004) Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA 292:81–85. https://doi.org/10.1001/jama.292.1.81

    Article  CAS  PubMed  Google Scholar 

  40. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G (2005) Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 35:1482–1490. https://doi.org/10.1002/eji.200425405

    Article  CAS  PubMed  Google Scholar 

  41. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553. https://doi.org/10.1128/mcb.25.21.9543-9553.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nematian SE, Mamillapalli R, Kadakia TS, Majidi Zolbin M, Moustafa S, Taylor HS (2018) Systemic inflammation induced by microRNAs: endometriosis-derived alterations in circulating microRNA 125b–5p and Let-7b-5p regulate macrophage cytokine production. J Clin Endocrinol Metab 103:64–74. https://doi.org/10.1210/jc.2017-01199

    Article  PubMed  Google Scholar 

  43. Bellelis P, Barbeiro DF, Rizzo LV, Baracat EC, Abrao MS, Podgaec S (2013) Transcriptional changes in the expression of chemokines related to natural killer and T-regulatory cells in patients with deep infiltrative endometriosis. Fertil Steril 99:1987–1993. https://doi.org/10.1016/j.fertnstert.2013.02.038

    Article  CAS  PubMed  Google Scholar 

  44. Kitaya K, Nakayama T, Daikoku N, Fushiki S, Honjo H (2004) Spatial and temporal expression of ligands for CXCR3 and CXCR4 in human endometrium. J Clin Endocrinol Metab 89:2470–2476. https://doi.org/10.1210/jc.2003-031293

    Article  CAS  PubMed  Google Scholar 

  45. Leconte M, Chouzenoux S, Nicco C, Chereau C, Arkwright S, Santulli P, Weill B, Chapron C, Dousset B, Batteux F (2014) Role of the CXCL12-CXCR4 axis in the development of deep rectal endometriosis. J Reprod Immunol 103:45–52. https://doi.org/10.1016/j.jri.2013.12.121

    Article  CAS  PubMed  Google Scholar 

  46. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA (1996) A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med 184:1101–1109. https://doi.org/10.1084/jem.184.3.1101

    Article  CAS  PubMed  Google Scholar 

  47. Hattori K, Heissig B, Tashiro K, Honjo T, Tateno M, Shieh JH, Hackett NR, Quitoriano MS, Crystal RG, Rafii S, Moore MA (2001) Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 97:3354–3360. https://doi.org/10.1182/blood.v97.11.3354

    Article  CAS  PubMed  Google Scholar 

  48. Cheng JW, Sadeghi Z, Levine AD, Penn MS, von Recum HA, Caplan AI, Hijaz A (2014) The role of CXCL12 and CCL7 chemokines in immune regulation, embryonic development, and tissue regeneration. Cytokine 69:277–283. https://doi.org/10.1016/j.cyto.2014.06.007

    Article  CAS  PubMed  Google Scholar 

  49. Kim CH, Broxmeyer HE (1998) In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment. Blood 91:100–110

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author notes

  1. Peng Chen and Ramanaiah Mamillapalli have contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar Street, New Haven, CT, 06510, USA

    Peng Chen, Ramanaiah Mamillapalli, Shutaro Habata & Hugh S. Taylor

  2. Obstetrics and Gynecology Department, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China

    Peng Chen

Authors
  1. Peng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ramanaiah Mamillapalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shutaro Habata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugh S. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

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

Correspondence to Ramanaiah Mamillapalli.

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

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

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-04012-1

Keywords

Search

Navigation