Endometriosis Cell Proliferation Induced by Bone Marrow Mesenchymal Stem Cells

Endometriosis is an estrogen-dependent gynecological disorder that affects 10% of reproductive-aged women and causes pelvic pain and infertility. Bone marrow–derived stem cells (BMDCs) are known to engraft endometriosis in association with lesion growth; however, they do not undergo significant clonal expansion. The indirect effects of BMDCs on endometriosis growth and cell proliferation are not well characterized. Here, we demonstrate that BMDCs’ co-culture increased endometrial stromal cell proliferation. In vitro studies using endometrial cells showed that BMDCs increased cell proliferation and activation of CDK1 in both an endometriosis cell line and primary endometrial stromal cells from women with endometriosis, however not in normal endometrial cells. In vivo studies using a mouse model of endometriosis showed increased CDK1+ expression associated with engrafted GFP + BMDCs. These results suggest that endometrial cell proliferation is induced by stem cell–derived trophic factors leading to the growth of endometriotic lesions. Targeting the specific signaling molecules secreted by BMDC may lead to novel therapeutic strategies for controlling cell proliferation in endometriosis. Similar content being viewed by others

Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–98. Taylor HS, Osteen KG, Bruner-Tran KL, et al. Novel therapies targeting endometriosis. Reprod Sci. 2011;18(9):814–23. Pluchino N, Taylor HS. Endometriosis and stem cell trafficking. Reprod Sci. 2016;23(12):1616–9. Taylor HS. Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA. 2004;292(1):81–5. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells. 2007;25(8):2082–6. Sakr S, Naqvi H, Komm B, Taylor HS. 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. 2014;155(4):1489–97. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016;7(1):125. Lebovic DI, Chao VA, Martini JF, Taylor RN. IL-1beta induction of RANTES (regulated upon activation, normal T cell expressed and secreted) chemokine gene expression in endometriotic stromal cells depends on a nuclear factor-kappaB site in the proximal promoter. J Clin Endocrinol Metab. 2001;86(10):4759–64. Hornung D, Klingel K, Dohrn K, Kandolf R, Wallwiener D, Taylor RN. Regulated on activation, normal T-cell-expressed and -secreted mRNA expression in normal endometrium and endometriotic implants: assessment of autocrine/paracrine regulation by in situ hybridization. Am J Pathol. 2001;158(6):1949–54. Halme J, Becker S, Hammond MG, Raj MH, Raj S. Increased activation of pelvic macrophages in infertile women with mild endometriosis. Am J Obstet Gynecol. 1983;145(3):333–7. Laird SM, Li TC, Bolton AE. The production of placental protein 14 and interleukin 6 by human endometrial cells in culture. Hum Reprod. 1993;8(6):793–8. Bersinger NA, Frischknecht F, Taylor RN, Mueller MD. Basal and cytokine-stimulated production of epithelial neutrophil activating peptide-78 (ENA-78) and interleukin-8 (IL-8) by cultured human endometrial epithelial and stromal cells. Fertil Steril. 2008;89(5 Suppl):1530–6. Bersinger NA, Gunthert AR, McKinnon B, Johann S, Mueller MD. Dose-response effect of interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, and interferon-gamma on the in vitro production of epithelial neutrophil activating peptide-78 (ENA-78), IL-8, and IL-6 by human endometrial stromal cells. Arch Gynecol Obstet. 2011;283(6):1291–6. Badawy SZ, Marshall L, Cuenca V. Peritoneal fluid prostaglandins in various stages of the menstrual cycle: role in infertile patients with endometriosis. Int J Fertil. 1985;30(2):48–52. Wu MH, Wang CA, Lin CC, Chen LC, Chang WC, Tsai SJ. Distinct regulation of cyclooxygenase-2 by interleukin-1beta in normal and endometriotic stromal cells. J Clin Endocrinol Metab. 2005;90(1):286–95. Santulli P, Borghese B, Chouzenoux S, Streuli I, Borderie D, de Ziegler D, et al. Interleukin-19 and interleukin-22 serum levels are decreased in patients with ovarian endometrioma. Fertil Steril. 2013;99(1):219–26. McKinnon BD, Kocbek V, Nirgianakis K, Bersinger NA, Mueller MD. Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics. Hum Reprod Update. 2016;22(3):382–403. Ryan IP, Schriock ED, Taylor RN. Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab. 1994;78(3):642–9. Noble LS, Takayama K, Zeitoun KM, et al. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab. 1997;82(2):600–6. Barr A, Manning D. G proteins techniques of analysis. Boca Raton: CRC Press, Inc; 1999. p. 227–45. Tal R, Liu Y, Pluchino N, Shaikh S, Mamillapalli R, Taylor HS. A murine 5-fluorouracil-based Submyeloablation model for the study of bone marrow-derived cell trafficking in reproduction. Endocrinology. 2016;157(10):3749–59. Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80(1):79–85. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3(2):93–110 143. Meresman GF, Vighi S, Buquet RA, Contreras-Ortiz O, Tesone M, Rumi LS. Apoptosis and expression of Bcl-2 and Bax in eutopic endometrium from women with endometriosis. Fertil Steril. 2000;74(4):760–6. Wang C, Jin A, Huang W, Tsang LL, Cai Z, Zhou X, et al. Up-regulation of Bcl-2 by CD147 through ERK activation results in abnormal cell survival in human endometriosis. J Clin Endocrinol Metab. 2015;100(7):E955–63. Korkmaz D, Bastu E, Dural O, Yasa C, Yavuz E, Buyru F. Apoptosis through regulation of Bcl-2, Bax and Mcl-1 expressions in endometriotic cyst lesions and the endometrium of women with moderate to severe endometriosis. J Obstet Gynaecol. 2013;33(7):725–8. Pellegrini C, Gori I, Achtari C, Hornung D, Chardonnens E, Wunder D, et al. The expression of estrogen receptors as well as GREB1, c-MYC, and cyclin D1, estrogen-regulated genes implicated in proliferation, is increased in peritoneal endometriosis. Fertil Steril. 2012;98(5):1200–8. Yotova IY, Quan P, Leditznig N, Beer U, Wenzl R, Tschugguel W. Abnormal activation of Ras/Raf/MAPK and RhoA/ROCKII signalling pathways in eutopic endometrial stromal cells of patients with endometriosis. Hum Reprod. 2011;26(4):885–97. Mei J, Li MQ, Ding D, Li DJ, Jin LP, Hu WG, et al. Indoleamine 2,3-dioxygenase-1 (IDO1) enhances survival and invasiveness of endometrial stromal cells via the activation of JNK signaling pathway. Int J Clin Exp Pathol. 2013;6(3):431–44. Abe W, Nasu K, Nakada C, Kawano Y, Moriyama M, Narahara H. miR-196b targets c-myc and Bcl-2 expression, inhibits proliferation and induces apoptosis in endometriotic stromal cells. Hum Reprod. 2013;28(3):750–61. Kawano Y, Nasu K, Hijiya N, Tsukamoto Y, Amada K, Abe W, et al. CCAAT/enhancer-binding protein alpha is epigenetically silenced by histone deacetylation in endometriosis and promotes the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2013;98(9):E1474–82. Moridi I, Mamillapalli R, Cosar E, Ersoy GS, Taylor HS. Bone marrow stem cell chemotactic activity is induced by elevated CXCl12 in endometriosis. Reprod Sci. 2017;24(4):526–33. Santamaria X, Mas A, Cervello I, Taylor H, Simon C. Uterine stem cells: from basic research to advanced cell therapies. Hum Reprod Update. 2018;24(6):673–93. Herraiz S, Buigues A, Diaz-Garcia C, et al. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril. 2018;109(5):908–18 e902. Alawadhi F, Du H, Cakmak H, Taylor HS. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman’s syndrome. PLoS One. 2014;9(5):e96662. Keaton MA. Review of “the cell cycle: principles of control” by David O. Morgan. Cell Div. 2007;2:27. Yang Y, Xue K, Li Z, Zheng W, Dong W, Song J, et al. [Corrigendum] c-Myc regulates the CDK1/cyclin B1 dependent-G2/M cell cycle progression by histone H4 acetylation in Raji cells. Int J Mol Med. 2019;44(5):1988. Chen X, Zhang FH, Chen QE, et al. The clinical significance of CDK1 expression in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. 2015;20(1):e7–12. Wang LL, Sun KX, Wu DD, Xiu YL, Chen X, Chen S, et al. DLEU1 contributes to ovarian carcinoma tumourigenesis and development by interacting with miR-490-3p and altering CDK1 expression. J Cell Mol Med. 2017;21(11):3055–65. Sung WW, Lin YM, Wu PR, Yen HH, Lai HW, Su TC, et al. High nuclear/cytoplasmic ratio of Cdk1 expression predicts poor prognosis in colorectal cancer patients. BMC Cancer. 2014;14:951. Tsaur I, Makarevic J, Hudak L, et al. The cdk1-cyclin B complex is involved in everolimus triggered resistance in the PC3 prostate cancer cell line. Cancer Lett. 2011;313(1):84–90. Zhou J, Han S, Qian W, Gu Y, Li X, Yang K. Metformin induces miR-378 to downregulate the CDK1, leading to suppression of cell proliferation in hepatocellular carcinoma. Onco Targets Ther. 2018;11:4451–9. Tang L, Wang TT, Wu YT, Zhou CY, Huang HF. High expression levels of cyclin B1 and polo-like kinase 1 in ectopic endometrial cells associated with abnormal cell cycle regulation of endometriosis. Fertil Steril. 2009;91(4):979–87. Funding This work was supported by the Endometriosis Foundation of America AWD0003567. Author information Authors and Affiliations Corresponding author Ethics declarations Conflict of Interest The authors declare that they have no conflict of interest. Ethics Approval Ethics involved in experiments carried out using cell lines approved by the Yale University. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic supplementary material ESM 1 (download DOCX ) Gross morphology of endometriotic lesions: Circles (white) indicate endometriotic lesions (left). H & E staining of lesion tissue section showing glandular uterine structure (right).(DOCX 11.7 kb) Rights and permissions About this article Cite this article Chen, P., Mamillapalli, R., Habata, S. et al. Endometriosis Cell Proliferation Induced by Bone Marrow Mesenchymal Stem Cells. Reprod. Sci. 28, 426–434 (2021). https://doi.org/10.1007/s43032-020-00294-4 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-020-00294-4