The ontogeny of myometrial stem cells in OCT4-GFP transgenic mouse model

Soumia Brakta,Ayman Al-Hendy,Aymara Mas

doi:10.1186/s13287-018-1079-7

Soumia Brakta, Ayman Al-Hendy + Show 1 more

Open Access

https://doi.org/10.1186/s13287-018-1079-7

Copy DOI

Abstract

BackgroundMyometrium, the muscular wall of the uterus, is an active organ markedly remodeled during a woman’s reproductive life, especially during pregnancy. Different studies using the 5-bromo-2′-deoxyuridine and side population methods in murine and human myometrium have suggested the presence of somatic stem cells in this tissue because of its remarkable regenerative capacity. Recently, our group has developed a surface-marker (Stro1/CD44)-specific approach to isolate and characterize myometrial somatic stem cells (SSCs) from humans and rats.ObjectiveIn this study, we aimed to identify and localize the putative myometrial stem cell population in the murine uterus by using the specific surface markers, Nanog/CD44.MethodsUteri from OCT4-GFP transgenic mice at different early-life time points were analyzed via single and double immunohistochemistry to co-localize myometrial stem cell marker CD44 with other general stemmness markers, e.g., Nanog and Oct-4. Finally, we correlated the frequency of myometrial stem cells in vivo with the expression of sex steroid hormone receptors, estrogen receptor α (ERα), and progesterone receptors A and B (PR A&B).ResultsNanog+/CD44+ stem cells were present in murine myometrium. Both stem cell markers were shown to co-localize with Oct-4 expression. Time-course experiments demonstrated that their percentages were significantly lower at the pre-sexual age of 1 week than at the sexually mature ages of 3 to 24 weeks. Importantly, both ERα and PR A&B were abundantly expressed in the myometrium at ages 1, 3 and 4 weeks.ConclusionsWe demonstrated that murine CD44+ myometrial cells have features of somatic stem cells with the expression of typical undifferentiated markers. Furthermore, our results suggest that myometrial stem cells are sex steroid hormone dependent, likely via paracrine pathway, and increase in numbers with reproductive maturity and rise in serum estrogen and progesterone levels around 3 weeks of age in mice. The abundance and early onset expression of ER/PR emphasize the vulnerability of neonatal myometrium to environmental endocrine disruptors which can potentially lead to permanent reprograming and adult onset of myometrial disorders such as uterine fibroids.

Highlights

Myometrium, the muscular wall of the uterus, is an active organ markedly remodeled during a woman’s reproductive life, especially during pregnancy
Our results suggest that myometrial stem cells are sex steroid hormone dependent, likely via paracrine pathway, and increase in numbers with reproductive maturity and rise in serum estrogen and progesterone levels around 3 weeks of age in mice
Histological examination for sex steroid hormone receptors To study the possible effect of ovarian sex steroids on the quantity of stem cells, we evaluated myometrial expression of estrogen receptor α (ERα) and progesterone receptors A and B (PR Progesterone receptors A and B (A&B)) at ages 1, 3, and 4 weeks using inverted microscopy

Summary

Introduction

Myometrium, the muscular wall of the uterus, is an active organ markedly remodeled during a woman’s reproductive life, especially during pregnancy. Tissue-specific stem cells called adult or somatic stem cells (SSCs) remain throughout the body for life. These adult SSCs are master cells that, through asymmetric division, retain their ability to self-renew while producing daughter cells that are the functional units of that tissue [1, 2]. The myometrium is the smooth muscle layer of the uterus, oftentimes characterized by its ability to remodel and regenerate during and after pregnancy [11, 12] These unique properties suggest the presence of myometrial stem cells that tightly regulate myometrial growth [3, 4]. The transformation of a normal myometrial stem cell into a leiomyoma-forming stem cell is likely a result of a complex process entailing multiple insults to the myometrial stem cell including hypoxic niche, altered epigenome, and abnormal estrogen signaling

Methods

Results

Discussion

Conclusion