INTRODUCTION
The endometrium is a unique tissue with a high reconstitution potential during the menstrual cycle throughout the women’s reproductive life. This high regenerative potential seems to be due to the presence of somatic stem cells (SSCs) residing in the endometrial niche inside this tissue. Apart from this endogenous source, an exogenous source of stem cells composed by bone marrow-derived stem cells (BMDSCs) is postulated to exist. The endometrial contribution of bone marrow has been described in healthy and diseased women. Specifically, transplanted BMDSCs release soluble factors under tissue damage that contribute to tissue repair. To be able to differentiate both populations of stem cells, endogenous and exogenous sources, screening of specific SSC markers would allow us to locate the endogenous stem cell pool inside the tissue and, therefore, to locate the endometrial stem cell niche. However, a universal endometrial SSC marker has not been described so far.
OBJECTIVES
With this background our aim was, first, to test postulated human SSC markers contributing to endometrial reconstruction in a murine model as endogenous reservoir, in order to identify a specific endometrial SSC marker. In addition, we aimed to study the role of regenerative factors released by BMDSCs as exogenous origin in women with endometrial pathologies.
MATERIALS AND METHODS
A xenotransplantation model was carried out by injecting several cell subsets (according to SSC markers ICAM1, W5C5 and Side Population, SP) under the kidney capsule of immunocompromised female mice. The characterization of the newly formed tissue was performed by the expression of three endometrial markers: vimentin, cytokeratin 18 and progesterone receptor, as well as by the endometrial SSC marker Musashi-1. We also studied these stem cell populations in endometriosis samples to study its relation with the disease. In parallel, we tried to identify paracrine factors released by BMDSCs transplanted in women with Asherman’s syndrome and/or endometrial atrophy.
RESULTS AND DISCUSSION
For the stem cell markers’ part, we obtained that positive cells for W5C5 and ICAM1 need the supplementation with total endometrial cells as support or niche-like cells to improve the reconstitution efficiency, probably mimicking the endometrial stem cell niche and promoting the undifferentiated state. Moreover, the Side Population is a heterogeneous population that would harbor a stem cell population in human endometrium, supported by the high regeneration capability demonstrated in the animal model. Regarding to paracrine factors involved in endometrial regeneration, we obtained that downregulated genes are implied in immune response, inflammation and apoptosis, while upregulated ones are involved in cell growth, angiogenesis, migration, differentiation and tissue repair, being midkine a good candidate as paracrine factor responsible for endometrial regeneration.
CONCLUSSIONS
1. The xenotransplantation model demonstrated that pure “putative stem cell populations” like W5C5+ and ICAM1+ from the human endometrium do not have the ability to efficiently reconstruct endometrium.
2. Supplementing with total endometrial cell fraction must include niche-like/neighbor cells belonging to the stem cell niche that would enhance the regenerative potential of pure “putative stem cell populations”.
3. The Side Population is a heterogeneous population harboring stem cells in the human endometrium, because of its high regeneration capability demonstrated in the animal model.
4. The identification of specific endometrial stem cell markers, as endogenous source, is essential for the study of endometrial biology, stem cell isolation, and the understanding of endometrial pathologies.
5. Exogenous stem cells secrete multiple factors that may exert a therapeutic effect via paracrine actions, as we observed after treating patients suffering from endometrial pathologies with bone marrow stem cells.
6. Stem cells secreted factors could exogenously promote the regulation of the PI3K-Akt pathway, which is associated with the maintenance of multipotency in mesenchymal stem cells.
7. The genes downregulated after cell therapy may imply an immunomodulatory scenario favoring this tissue remodeling. In contrast, the upregulated ones (including MK) are implicated in cell growth, angiogenesis, migration, differentiation and tissue repair.
8. These factors secreted by transplanted cells may influence the microenvironment or activate endometrial somatic stem cells for tissue regeneration
