Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis

Abstract

Endometrial stem/progenitor cells have been proved to exist in periodically regenerated female endometrium and can be divided into three categories: endometrial epithelial stem/progenitor cells, CD140b+CD146+ or SUSD2+ endometrial mesenchymal stem cells (eMSCs), and side population cells (SPs). Endometrial stem/progenitor cells in the menstruation blood are defined as menstrual stem cells (MenSCs). Due to their abundant sources, excellent proliferation, and autotransplantation capabilities, MenSCs are ideal candidates for cell-based therapy in regenerative medicine, inflammation, and immune-related diseases. Endometrial stem/progenitor cells also participate in the occurrence and development of endometriosis by entering the pelvic cavity from retrograde menstruation and becoming overreactive under certain conditions to form new glands and stroma through clonal expansion. Additionally, the limited bone marrow mesenchymal stem cells (BMDSCs) in blood circulation can be recruited and infiltrated into the lesion sites, leading to the establishment of deep invasive endometriosis. On the other hand, cell derived from endometriosis may also enter the blood circulation to form circulating endometrial cells (CECs) with stem cell-like properties, and to migrate and implant into distant tissues. In this manuscript, by reviewing the available literature, we outlined the characteristics of endometrial stem/progenitor cells and summarized their roles in immunoregulation, regenerative medicine, and endometriosis, through which to provide some novel therapeutic strategies for reproductive and cancerous diseases.

Immunopathogenesis of endometriosis – a novel look at an old problem

“…The risk factors of endometriosis may involve: 1) women's age; 2) heavy but short menses [7]; 3) low body mass index [13]; 4) psychological and emotional factors; 5) stress and/a pain response in pelvis; 6) nulliparity; 7) high education and social level [3]. Patients with endometriosis have a high risk for systemic comorbidities including autoimmune, cardiovascular and atopic diseases.…”

“…Although the pathogenesis of endometriosis is still debated, evidence indicates that both the onset and the progression of this disease are supported by: 1) an imbalance of invasive, proliferative and adhesive properties of endometrial cells; 2) increased production of inflammatory molecules [1]. Currently, the most accepted theory seems to be Sampson's retrograde menstruation hypothesis, which suggests that during menstruation, endometrial fragments migrate through the Fallopian tubes to the peritoneal cavity and reach the peritoneum, as they are able to attach, survive, and implant in different locations (Fallopian tubes, ovaries, and pouch of Douglas) [2,[7][8][9].…”

Understanding menstrual blood-derived stromal/stem cells: Definition and properties. Are we rushing into their therapeutic applications?

“…Basic science experts reiterate the importance of an exhaustive and undirected characterization of the cells before their application ( Galipeau and Sensebe, 2018 ). However, several studies have already shown the regenerative, reparative, and protective properties of eMSCs and recently also of MenSCs ( Chen et al., 2019 ; Kong et al., 2021 ).…”

“…Taken together, MenSCs have a variety of effects on both the innate and specific immune responses that have been extensively reviewed ( Bozorgmehr et al., 2020 ; Kong et al., 2021 ) and are not the focus of this study. They show inconsistencies between in vitro and in vivo findings and a considerable variation among experimental models, needing further investigation to identify the underlying mechanisms that organize the dialogue that MenSC use to modulate the immune system.…”

“…As mentioned, the paracrine effect of MenSCs in regenerative or reparative medicine has been analyzed recently as an attractive source with potential clinical applications. Several studies have shown that MenSCs repair damaged tissues and promote functional recovery through paracrine effects rather than cell differentiation ( Bozorgmehr et al., 2020 ; Kong et al., 2021 ). Their reparative potential has been shown in several diseases such as myocardial infarction rat models ( Hida et al., 2008 ; Jiang et al., 2013 ; Liu et al., 2019 ) where intracardiac MenSC transplantation improved left ventricular systolic function and fibrotic areas ( Hida et al., 2008 ), reduced cell apoptosis, and increased cell proliferation primarily by the effect of secreted cytokines including PDGF, EGF, nitric oxide (NO), and TGF-β2 on AKT and STAT3 signaling activation.…”