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Altered differentiation of endometrial mesenchymal stromal fibroblasts is associated with endometriosis susceptibility.

ABSTRACT: Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with (n = 10) and without (n = 9) endometriosis we analysed the transcriptome of 33,758 individual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.

SUBMITTER: McKinnon BD

PROVIDER: S-EPMC9209414 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Altered differentiation of endometrial mesenchymal stromal fibroblasts is associated with endometriosis susceptibility.

McKinnon Brett D BD Lukowski Samuel W SW Mortlock Sally S Crawford Joanna J Atluri Sharat S Subramaniam Sugarniya S Johnston Rebecca L RL Nirgianakis Konstantinos K Tanaka Keisuke K Amoako Akwasi A Mueller Michael D MD Montgomery Grant W GW

Communications biology 20220620 1

Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not ...[more]

PMID: 35725766

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Project description:BackgroundThis study aims to investigate the effects of carob (Ceratonia siliqua L.) pod extract (CPE) on the viability of human endometrial mesenchymal stromal/stem cells (EnMSCs) and its impact on mRNA and protein expressions of DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B), histone deacetylase 1 (HDAC1), matrix metalloproteinase-2 (MMP2), and cyclooxygenase-2 (COX-2) in endometriotic patients.Materials and methodsIn this experimental study, EnMSCs were derived from endometrium of patients with ovarian endometrioma (OMA-EnMSCs group) and deep infiltrative endometriosis (DIE) samples of 10 endometriosisassociated infertility (EAI) women (E-EnMSCs group) and compared to EnMSCs derived from the endometrium of an endometriosis-free, normal woman as the control group (C-EnMSCs). The metabolic activity of the control and case groups were evaluated by treating them with different concentrations of CPE. Cell viability was analysed by MTT. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to evaluate the expression of specific genes at the mRNA and protein levels, respectively.ResultsTreatment with 0.8 and 2 μg/mL of CPE downregulated COX-2 and HDAC1 in the E-EnMSC group compared to the C-EnMSCs group. Treatment with 0.8 μg/mL of CPE also decreased MMP2 and DNMT3B gene expressions. The COX-2 and DNMT3A genes were significantly upregulated after treatment with 2 μg/mL of CPE. Expressions of the COX-2, HDAC1, DNMT1, DNMT3A, and DNMT3B peptides decreased in the all three groups after treatment with 0.8 and 2 μg/mL of CPE. Gas chromatography-mass spectroscopy (GC-MS) analysis of CPE identified 14 bioactive compounds. Molecular docking showed the best position of each bioactive compound on the different target proteins that are involved in the process of apoptosis in EnMSCs.ConclusionIn vitro and in silico analyses of CPE bioactive compounds show that they may downregulate the cell inflammatory pathway involved in the pathophysiology of endometriosis.

Project description:Consistency in clinical outcomes is key to the success of therapeutic Mesenchymal Stem/Stromal cells (MSCs) in regenerative medicine. MSCs are used to treat both humans and companion animals (horses, dogs, and cats). The properties of MSC preparations can vary significantly with factors including tissue of origin, donor age or health status. We studied the effects of developmental programming associated with intrauterine growth restriction (IUGR) on MSC properties, particularly related to multipotency. IUGR results from inadequate uterine capacity and placental insufficiency of multifactorial origin. Both companion animals (horses, dogs, cats) and livestock (pigs, sheep, cattle) can be affected by IUGR resulting in decreased body size and other associated changes that can include, alterations in musculoskeletal development and composition, and increased adiposity. Therefore, we hypothesized that this dysregulation occurs at the level of MSCs, with the cells from IUGR animals being more prone to differentiate into adipocytes and less to other lineages such as chondrocytes and osteocytes compared to those obtained from normal animals. IUGR has consequences on health and performance in adult life and in the case of farm animals, on meat quality. In humans, IUGR is linked to increased risk of metabolic (type 2 diabetes) and other diseases (cardiovascular), later in life. Here, we studied porcine MSCs where IUGR occurs spontaneously, and shows features that recapitulate human IUGR. We compared the properties of adipose-derived MSCs from IUGR (IUGR-MSCs) and Normal (Normal-MSCs) new-born pig littermates. Both MSC types grew clonally and expressed typical MSC markers (CD105, CD90, CD44) at similar levels. Importantly, tri-lineage differentiation capacity was significantly altered by IUGR. IUGR-MSCs had higher adipogenic capacity than Normal-MSCs as evidenced by higher adipocyte content and expression of the adipogenic transcripts, PPARγ and FABP4 (P < 0.05). A similar trend was observed for fibrogenesis, where, upon differentiation, IUGR-MSCs expressed significantly higher levels of COL1A1 (P < 0.03) than Normal-MSCs. In contrast, chondrogenic and osteogenic potential were decreased in IUGR-MSCs as shown by a smaller chondrocyte pellet and osteocyte staining, and lower expression of SOX9 (P < 0.05) and RUNX2 (P < 0.02), respectively. In conclusion, the regenerative potential of MSCs appears to be determined prenatally in IUGR and this should be taken into account when selecting cell donors in regenerative therapy programmes both in humans and companion animals.

Dataset Information

Altered differentiation of endometrial mesenchymal stromal fibroblasts is associated with endometriosis susceptibility.

Publications

Altered differentiation of endometrial mesenchymal stromal fibroblasts is associated with endometriosis susceptibility.

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