Niche matters: The comparison between bone marrow stem cells and endometrial stem cells and stromal fibroblasts reveal distinct migration and cytokine profiles in response to inflammatory stimulus

April Niche matters: The comparison between bone marrow stem cells and endometrial stem cells and stromal fibroblasts reveal distinct migration and cytokine profiles in response to inflammatory stimulus Masuma Khatun 0 1 2 Anna Sorjamaa 0 1 2 Marika Kangasniemi 0 1 2 Meeri Sutinen 0 2 Tuula Salo 0 2 Annikki Liakka 0 2 Petri Lehenkari 0 2 3 Juha S. Tapanainen 0 1 2 Olli Vuolteenaho 0 2 Joseph C. Chen 0 2 Siri Lehtonen 0 1 2 Terhi T. Piltonen 0 1 2 0 Juselius Foundation, Academy of Finland, Finnish Medical Foundation, and Orion-Farmos Research Foundation 1 Department of Obstetrics and Gynecology, PEDEGO Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital , Oulu , Finland , 2 Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Oulu University Hospital , Oulu , Finland , 3 Department of Pathology, Medical Research Center, University of Oulu and Oulu University Hospital , Oulu , Finland 2 Editor: Giovanni Camussi, Universita degli Studi di Torino , ITALY 3 Department of Anatomy and Department of Internal Medicine, Medical Research Center, University of Oulu and Oulu University Hospital , Oulu , Finland , 5 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital , Helsinki , Finland , 6 Research Unit of Biomedicine, University of Oulu , Oulu , Finland , 7 Department of Obstetrics, Gynecology and Reproductive Sciences, University of California , San Francisco , United States of America - Data Availability Statement: All relevant data are within the paper. Competing interests: The authors have declared that no competing interests exist. Objective Intrinsic inflammatory characteristics play a pivotal role in stem cell recruitment and homing through migration where the subsequent change in niche has been shown to alter these characteristics. The bone marrow mesenchymal stem cells (bmMSCs) have been demonstrated to migrate to the endometrium contributing to the stem cell reservoir and regeneration of endometrial tissue. Thus, the aim of the present study was to compare the inflammation-driven migration and cytokine secretion profile of human bmMSCs to endometrial mesenchymal stem cells (eMSCs) and endometrial fibroblasts (eSFs). Materials and methods The bmMSCs were isolated from bone marrow aspirates through culturing, whereas eMSCs and eSFs were FACS-isolated. All cell types were tested for their surface marker, proliferation profiles and migration properties towards serum and inflammatory attractants. The cytokine/chemokine secretion profile of 35 targets was analysed in each cell type at basal level along with lipopolysaccharide (LPS)-induced state. Results Both stem cell types, bmMSCs and eMSCs, presented with similar stem cell surface marker profiles as well as possessed high proliferation and migration potential compared to eSFs. In multiplex assays, the secretion of 16 cytokine targets was detected and LPS stimulation expanded the cytokine secretion pattern by triggering the secretion of several targets. The bmMSCs exhibited higher cytokine secretion of vascular endothelial growth factor (VEGF)A, stromal cell-derived factor-1 alpha (SDF)-1α, interleukin-1 receptor antagonist (IL-1RA), IL-6, interferon-gamma inducible protein (IP)-10, monocyte chemoattractant protein (MCP)1, macrophage inflammatory protein (MIP)1α and RANTES compared to eMSCs and/or eSFs after stimulation with LPS. The basal IL-8 secretion was higher in both endometrial cell types compared to bmMSCs. Conclusion Our results highlight that similar to bmMSCs, the eMSCs possess high migration activity while the differentiation process towards stromal fibroblasts seemed to result in loss of stem cell surface markers, minimal migration activity and a subtler cytokine profile likely contributing to normal endometrial function. Introduction The human endometrium has a unique ability to regenerate rapidly, increasing its thickness from 2±4 mm in the early proliferative phase to 10±15 mm by the end of the secretory phase [ 1,2 ]. The growth of the endometrial tissue is under steroid hormone (estradiol [E2] and progesterone [P4]) control, where the monthly cycles of growth, differentiation and shedding occur in response to ovarian hormonal fluctuations [3]. With blastocyst implantation, the endometrium is challenged with immune tolerance, the regulation of trophoblast invasion and vasculature formation, in which a balanced hormonal and immune environment, the niche is crucial for successful and healthy pregnancy [4±6]. In a non-conception cycle, the endometrium goes through a complex inflammatory process involving cell drift and immune cell migration leading to the activation of degradative enzymes and apoptosis, subsequent tissue breakdowns and menstruation. Simultaneously, the molecular processes ensuring tissue regeneration, revascularization and histoarchitectural development are initiated, most likely th (...truncated)