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ALDH1A1+ cells are endometrial progenitors contributing to regeneration and endometriosis [mouse]

ABSTRACT: Endometrial stem cells and their regenerative properties are implicated in the pathogenesis of endometriosis. Using single-cell RNA sequencing of the adult mouse endometrial epithelium, we identified a sub-population of aldehyde dehydrogenase 1a1+ (Aldh1a1+) stem-like cells that co-expresses stemness genes (Lgr5, Axin2) and lack proliferative markers (Top2a, Mki67). Using an Aldh1a1cre/ERT2;ROSA26tdTomato reporter mouse, we found that Aldh1a1+ cells give rise to long-lived endometrial cells and contribute to post-partum endometrial repair. Selective ablation of ALDH1A1+ cells with diphtheria toxin (DT) in Aldh1a1cre/ERT2; ROSA26-DTRflox/flox mice decreased glands and FOXA2 expression in vivo. Mouse and human ALDHHI endometrial cells had higher organoid formation capacity and stem-like gene signatures than ALDHLO cells. Ectopic lesion-derived organoids showed higher ALDH activity than patient-matched eutopic cells and displayed enriched pro-inflammatory, stemness, and ciliated cell transcriptomes. Here we provide evidence that ALDH1A1+ cells display progenitor/stem cell characteristics in the endometrium and contribute to the pathology of endometriosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE294256 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:An integrated systems approach was used with bioinformatics tools to understand the the role of aldehyde dehydrogenase 1A1 (ALDH1A1) in human colon cancer cells. We combined transcriptomics, proteomics and untargeted metabolomics to gain insight into the mechanisms affected by the suppression of the ALDH1A1 gene in COLO320 cells. RNA-seq and proteomics analyses revealed 1747 transcripts and 336 proteins that were differentially expressed in cells in which the ALDH1A1 had been suppressed by shRNA transfection. Transcriptomics pathway analysis showed significant signaling pathways, such as Wnt/β-catenin (p=3.47E-6), molecular mechanisms of cancer (7.41E-5) and others relevant to lipid metabolism, such as cholesterol biosynthesis I, II and III (p=1.82E-4). Proteomics pathway analysis identified oxidative phosphorylation to be the most highly significant pathway (p=5.01E-31). Pathway analysis of the genes common to the transcriptomics and proteomics analyses revealed the asparagine biosynthesis (p=3.16E-3) and cholesterol biosynthesis the most statistically significant (p=3.36E-3). Univariate analysis of the untargeted metabolomics dataset revealed 859 ions statistically significant. Network analysis showed alterations in pathways linked to energy and lipid metabolism, such carnitine shuttle (p=5.3E-4) and fatty acid oxidation (p=2.9E-2). A systems biology approach was used to integrate all three datasets and a total of 61 pathways were generated. A direct association between the suppression of ALDH1A1 and the Vitamin A (retinol) metabolism pathway and down-regulation of retinol and the UGT2B17, UGT2A3 and PRDX6 genes was shown. In conclusion, the present results confirm the role of ALDH1A1 in retinol metabolism and shows for the first time the influence of this gene on lipid metabolism pathways that may be crucial for cholesterol synthesis in human colon cancer cells. In addition, they demonstrate how an integrated systems approach using unbiased bioinformatics tools can be used to understand the interplay of cellular pathways.

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ALDH1A1+ cells are endometrial progenitors contributing to regeneration and endometriosis [mouse]

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