Abstract
BackgroundIn Asherman’s syndrome (AS), intrauterine scarring and fibrotic adhesions lead to menstrual disorders, pregnancy loss, or infertility. A few clinical trials have piloted cell therapy to overcome AS. Understanding the role of the stromal compartment in endometrial regeneration remains poorly understood. We hypothesize that endometrial stromal cells (eSCs) represent a relevant cell population to establish novel cell-based therapeutics for endometrial disorders. The aim of this study was to characterize eSCs and evaluate their immune-cell interactions.MethodseSCs were isolated from healthy donors, during the proliferative stage of the menstrual cycle. Cells were characterized for expression of mesenchymal stromal cell (MSC) markers and assessed for their tumorigenic potential. eSCs were co-cultured with interferon γ and tumor necrosis factor α, and cell surface expression of their respective receptors and human leukocyte antigen (HLA) I and II determined by flow cytometry. Secreted levels of key immunomodulatory factors were established. eSCs were cultured with activated peripheral blood mononuclear cells, and T cell differentiation and proliferation determined.ResultseSCs demonstrated an MSC surface phenotype and exhibited multipotency. Expanded eSCs retained chromosomal stability and demonstrated no tumorigenicity. Upon stimulation, eSCs licensed to an anti-inflammatory phenotype with upregulated secretion of immunomodulatory factors. Stimulated eSCs did not express HLA class II. eSCs suppressed the proliferation and activation of CD4+ T cells, with the eSC secretome further downregulating central memory T cells and upregulating effector memory (EM) cells.ConclusionsDifferential responsiveness to inflammation by eSCs, compared to other MSC sources, demonstrates the need to understand the specific functional effects of individual stromal cell sources. A lack of HLA class II and triggering of EM T cell differentiation strongly links to innate in vivo roles of eSCs in tissue repair and immune tolerance during pregnancy. We conclude that eSCs may be an ideal cell therapy candidate for endometrial disorders.
Highlights
In Asherman’s syndrome (AS), intrauterine scarring and fibrotic adhesions lead to menstrual disorders, pregnancy loss, or infertility
Cumulative growth kinetics supported this finding, demonstrating that all donors could be expanded for a minimum of 6 passages without entering replicative senescence
Using the International Society of Cellular Therapy (ISCT) mesenchymal stromal cell (MSC) guidelines [28] as a reference to characterize our cell product, we found ex vivo expanded Endometrial stromal cell (eSC) adhered to plastic; had positive (> 95%) cell surface marker expression for CD105, CD73, CD90, and human leukocyte antigen (HLA) I; and lacked expression of hematopoietic surface antigens CD45, CD34, CD14, CD19, and HLA II (< 2%)
Summary
In Asherman’s syndrome (AS), intrauterine scarring and fibrotic adhesions lead to menstrual disorders, pregnancy loss, or infertility. Healthy endometrium regenerates approximately 450 times in a women’s reproductive life without the formation of scar tissue [1]. The menstrual cycle and its 3 main stages, menstruation and the proliferative and secretory phases, have been likened to the phases of wound repair [5,6,7]. As seen in the dermis, is accompanied by the formation of tissue granulation and scar maturation [8]. In healthy endometrium, no Queckbörner et al Stem Cell Research & Therapy (2020) 11:15 scarring is observed, suggesting regenerative healing, more akin to the fetal-like response seen in the buccal mucosa of the oral cavity [9,10,11,12]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call