Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA.
Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Portland, OR, USA.
Biol Reprod. 2022 Sep 12;107(3):732-740. doi: 10.1093/biolre/ioac090.
The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane chloride/bicarbonate ion channel in epithelial cells. Mutations in CFTR cause cystic fibrosis, a disease characterized by thickened mucus secretions and is associated with subfertility and infertility. CFTR function has been well characterized in vitro and in vivo in airway and other epithelia studies. However, little is known about CFTR function in the cervix in health and its contribution to cyclic regulation of fertility from endocervical mucus changes. Contributing to this research gap is the lack of information on the effect of sex steroid hormones on CFTR expression in cervical epithelial cells across the menstrual cycle. Herein, we demonstrate the hormonal regulation of CFTR expression in endocervical cells both in vitro and in vivo, and that conditionally reprogrammed endocervical epithelial cells can be used to interrogate CFTR ion channel function. CFTR activity was demonstrated in vitro using electrophysiological methods and functionally inhibited by the CFTR-specific inhibitors inh-172 and GlyH-101. We also report that CFTR expression is increased by estradiol in the macaque cervix both in vitro and in vivo in Rhesus macaques treated with artificial menstrual cycles. Estrogen upregulation of CFTR is blocked in vivo by cotreatment with progesterone. Our findings provide the most comprehensive evidence to date that steroid hormones drive changes in CFTR expression. These data are integral to understanding the role of CFTR as a fertility regulator in the endocervix.
囊性纤维化跨膜电导调节因子（CFTR）是上皮细胞顶膜上的氯离子/碳酸氢根离子通道。CFTR 的突变会导致囊性纤维化，这是一种以黏液分泌增厚为特征的疾病，与生育力低下和不孕有关。CFTR 的功能已在气道和其他上皮细胞研究中得到了很好的体外和体内研究。然而，人们对健康宫颈中 CFTR 的功能知之甚少，也不知道它在宫颈黏液变化与生育周期循环调节方面的作用。造成这一研究空白的原因是缺乏关于性甾体激素对宫颈上皮细胞 CFTR 表达在月经周期中的影响的信息。在此，我们证明了 CFTR 在宫颈内细胞中的表达受激素的调节，无论是在体外还是在体内，并且条件重编程的宫颈上皮细胞可用于研究 CFTR 离子通道功能。CFTR 活性通过电生理学方法在体外进行了验证，并被 CFTR 特异性抑制剂 inh-172 和 GlyH-101 功能性抑制。我们还报告称，在恒河猴中，用人工月经周期处理后，雌二醇在体外和体内均增加了 CFTR 在宫颈中的表达。孕激素的体内共处理阻断了 CFTR 的雌激素上调。我们的发现提供了迄今为止最全面的证据，证明甾体激素驱动 CFTR 表达的变化。这些数据对于理解 CFTR 作为宫颈内生育调节因子的作用至关重要。
