title: Endometriotic mesenchymal stem cells exhibit a distinct immune phenotype.
abstract: Endometriosis is a significant debilitating gynecological problem affecting women of the reproductive age group and post-menopause. Recent reports suggest a role for endometriotic mesenchymal stem cells (ectopic MSCs) in the pathogenesis of endometriosis. To investigate the plausible mechanisms leading to the pathogenic behavior of ectopic MSCs, we compared the immunomodulatory properties of eutopic (healthy) and ectopic MSCs. We analyzed MSC phenotypes, differentiation potential, differential gene expression for an array of pattern recognition receptors (PRRs) and pro-inflammatory cytokine release along with markers of migration and angiogenesis among eutopic and ectopic MSCs. Further, alterations in immunosuppressive functions of eutopic and ectopic MSCs were examined by co-culturing them with mitogen-activated allogeneic PBMCs. Transcripts of PRRs such as all Toll-like receptors (TLR1-10), except TLR8, collectins (CL-L1, CL-P1 and CL-K1), NOD-1 and NOD-2 receptors and secreted pro-inflammatory cytokines like IL-6, IFN-γ, vascular endothelial growth factor (VEGF), epidermal growth factor and MCP-1 were significantly up-regulated in ectopic MSCs. The anti-inflammatory cytokine transforming growth factor-β showed significant down-regulation, while IL-10 showed a significant increase in ectopic MSCs. Further, ectopic MSCs showed up-regulated expression for markers of migration and angiogenesis such as matrix metalloproteinase-2 (MMP-2), MMP-3 and MMP-9 and VEGF, respectively. We report here that proliferation of PBMCs was less inhibited upon co-culture with ectopic MSCs compared with eutopic MSCs. The findings suggest that ectopic MSCs with increased levels of TLRs, collectins, pro-inflammatory cytokines and markers of migration and angiogenesis exhibit a distinct immune phenotype compared to eutopic MSCs. This distinct phenotype may be responsible for the reduced immunosuppressive property of ectopic MSCs and may be associated with the pathogenesis of endometriosis.
authors.affiliation: Department of Innate Immunity, National Institute for Research in Reproductive Health (ICMR), J. M. Street, Parel, Mumbai 400 012, India.
authors.forename: Aghila Rani
authors.initials: AR
authors.lastname: Koippallil Gopalakrishnan Nair
authors.affiliation: Department of Innate Immunity, National Institute for Research in Reproductive Health (ICMR), J. M. Street, Parel, Mumbai 400 012, India.
authors.forename: Hrishikesh
authors.initials: H
authors.lastname: Pandit
authors.affiliation: Department of Obstetrics and Gynecology, Sanjeevani Endoscopy and Gynecology Centre, Kandivali, Mumbai 400 101, India.
authors.forename: Neeta
authors.initials: N
authors.lastname: Warty
authors.affiliation: Department of Innate Immunity, National Institute for Research in Reproductive Health (ICMR), J. M. Street, Parel, Mumbai 400 012, India taruna_m@hotmail.com.
authors.forename: Taruna
authors.initials: T
authors.lastname: Madan
mesh_terms: D000328:Adult; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D037222:Collectins / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004715:Endometriosis / Q000276:immunology / Q000473:pathology*; D005260:Female; D006801:Humans; D056747:Immunomodulation / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000235:genetics; D010641:Phenotype; D051193:Toll-Like Receptors / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D037222:Collectins; D016207:Cytokines; D051193:Toll-Like Receptors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Toll-like receptors; endometriosis; immunomodulation; pattern recognition receptors; pro-inflammatory cytokines