Mouse uterine stem cells are affected by endocrine disruption and initiate uteropathies

Abstract

Underlying pathomechanisms leading to initiation of uteropathies including non-receptive endometrium, hyperplasia, adenomyosis, endometriosis, fibroids, and cancer remain elusive. Two populations of stem cells exist in mouse uterus including pluripotent, very small embryonic-like stem cells (VSELs) and ‘progenitors’ endometrial stem cells (EnSCs) which express ERα, ERβ, PR and FSHR, participate in the regular remodelling and maintain life-long homeostasis. The present study aimed to delineate possible stem cell origins for various uteropathies. For this mouse pups were treated with estradiol or diethylstilbestrol and were studied for adult onset of various uteropathies. Treatment resulted in disrupted estrous cycles, reduced uterine weights, and marked hyperplasia in both epithelial and myometrial compartments, and the stromal compartment was also affected. VSELs were increased in numbers as judged by flow cytometry and increased expression of transcripts specific for Oct-4A, Sox-2, and Nanog but their further differentiation into a receptive endometrium was affected. Reduced 5-methyl cytosine expression suggested global hypomethylation and was associated with several oncogenic events including loss of tumor suppressor genes (Pten, p53), dysregulated DNA mismatch repair axis, and repair enzymes. Stem cells were epigenetically altered and showed increased expression of DNMTs, loss of imprinting loci (Igf2-H19, Dlk1-Meg3), and Ezh2. Increased co-expression of CD166 and ALDHA1 with OCT-4 in stem cells was associated with increased Esr-2 and reduced Pr in the endometrium while both were several folds upregulated in the myometrium. Study results suggest that various uteropathies ensue due to the dysfunction of tissue-resident stem cells and provide huge scope for further research.