The ontogeny of myometrial stem cells in OCT4-GFP transgenic mouse model
The ontogeny of myometrial stem cells in OCT4-GFP transgenic mouse model
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DOI：
10.1186/s13287-018-1079-7
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发表时间：
2018-11-29
影响因子：
7.5
通讯作者：
Al-Hendy, Ayman
中科院分区：
文献类型：
--
作者：
Brakta, Soumia;Mas, Aymara;Al-Hendy, Ayman
背景子宫肌层是子宫的肌壁，是一个活跃的器官，在妇女的生殖生活中，特别是在怀孕期间，显著重塑。在小鼠和人子宫肌层中使用5-溴-2-脱氧尿苷和侧群方法的不同研究表明，由于其显著的再生能力，该组织中存在体干细胞。最近，我们的团队开发了一种表面标记（Stro 1/CD 44）特异性方法分离和鉴定人和大鼠子宫肌层干细胞（SSCs）在本研究中，我们旨在通过使用特异性表面标记来鉴定和定位小鼠子宫肌层干细胞群，方法采用免疫组织化学方法对OCT 4-GFP转基因小鼠早期子宫肌层干细胞标志物CD 44和其他干细胞标志物进行单、双标记共定位，例如，在一个实施例中，Nanog和Oct-4。最后，我们将子宫肌层干细胞在体内的频率与性类固醇激素受体、雌激素受体（ER）和孕激素受体A和B（PR A&B）的表达相关联。这两种干细胞标志物显示与Oct-4表达共定位。时程实验表明，性前1周龄的雌、雄、雄激素的比例显著低于性成熟3 ~ 24周龄的雌、雄激素的比例。结论CD 44（+）小鼠子宫肌层细胞具有体干细胞的特征，表达典型的未分化标志物。此外，我们的研究结果表明，子宫肌层干细胞是性类固醇激素依赖性的，可能通过旁分泌途径，并增加数量与生殖成熟和血清雌激素和孕激素水平上升约3周龄的小鼠。ER/PR的丰富和早发性表达强调了新生儿子宫肌层对环境内分泌干扰物的脆弱性，这可能导致永久性重编程和子宫肌层疾病如子宫肌瘤的成年发病。
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 (ER), 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 1week than at the sexually mature ages of 3 to 24weeks. Importantly, both ER and PR A&B were abundantly expressed in the myometrium at ages 1, 3 and 4weeks.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 3weeks 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.