Endometrial epithelial cells with high ALDH activity control uterine development and regeneration

Suni Tang, Anna Catherine Unser, Peixin Jiang, Sydney E Parks, Genesis J Herrera, Ting Geng, Linda Alpuing-Radilla, Brooke A Thigpen, Xiaoming Guan, Diana Monsivais
In: eLife · 2026 · doi:10.7554/elife.110975.1 · W7160403167
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

Cells with high aldehyde dehydrogenase 1 activity in the endometrium act as long-lived progenitors critical for uterine development and regeneration.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This study investigated whether endometrial epithelial cells with high aldehyde dehydrogenase activity (ALDHHI; ALDH1A1) represent adult stem/progenitor cells that drive uterine development and regeneration. Using FACS-sorted mouse ALDHHI versus ALDHLO populations, organoid formation and RNAseq showed ALDHHI cells had higher organoid formation capacity and distinctive transcriptomic patterns consistent with stemness, including increased expression of stem-related programs such as BMP receptor signaling and shared signatures with Axin2HI cells; the authors also performed lineage tracing showing Aldh1a1+ cell expansion during postnatal development, estrus cycling, and postpartum repair, with hormone-sensitive localization changes after ovariectomy or estradiol treatment. Selective ablation of Aldh1a1+ cells reduced endometrial gland number and FOXA2 expression, and human endometrial organoids with high ALDH activity similarly formed more organoids and had different epithelial transcriptomes with fewer luminal-like ciliated cells. A stated limitation is that the work defines ALDH activity/stemness mainly through organoid assays, transcriptomic signatures, and genetic ablation rather than fully resolving the precise molecular niche and downstream pathways in vivo. This paper is centrally about endometriosis — it frames adult endometrial stem cells as potentially contributing to endometriosis pathogenesis and cites ALDH1A1 enrichment in ectopic endometriotic lesions, linking ALDH1A1+ regenerative epithelial biology to mechanisms relevant to endometriosis.

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Abstract

Adult stem cells are thought to drive the regenerative potential of the endometrium and contribute to the pathogenesis of endometriosis, however, their identity and defining features remain to be characterized. Here, we used in vivo and in vitro approaches to demonstrate that cells with high aldehyde dehydrogenase 1 activity (ALDHHI cells) were long lived progenitors in the endometrial epithelium with a higher organoid formation capacity, long-term passaging potential, and stemness gene signatures. Using lineage tracing with an Aldh1a1cre/ERT2; ROSA26tdTomato reporter mouse, Aldh1a1+ cells expanded during postnatal development, estrus cycling, and following post-partum repair. In response to ovariectomy or exogenous estradiol, we found that ALDH1A1+ cells localized to glandular crypts of the endometrium or throughout the luminal epithelium, respectively, indicating that their spatial localization is hormone sensitive. Functionally, we found that selective ablation of ALDH1A1+ cells in Aldh1a1cre/ERT2; ROSA26-DTRflox/flox mice decreased endometrial gland number and FOXA2 expression. These findings were recapitulated in the human endometrium, where endometrial epithelial organoids with high ALDH activity (ALDHHI cells) showed a higher organoid formation capacity than ALDHLO cells and displayed unique transcriptomes with fewer luminal-like ciliated cells. Overall, our studies indicate that ALDH1A1+ cells are hormone-sensitive adult stem cells in the endometrium with regenerative potential that are critical for endometrial development and function.

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endometriosis

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