Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea.
Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Republic of Korea.
Cell Death Dis. 2021 Jun 12;12(6):612. doi: 10.1038/s41419-021-03893-4.
Chronic stress has a negative impact on many fertility-related functions; thus, the recent decline in female fertility seems to be at least partially associated with increased stress. The secretion of glucocorticoids is a typical endocrine response to chronic stress and indirectly reduces uterine receptivity through the hypothalamus-pituitary-gonadal (HPG) axis. However, in addition to its well-known canonical role, the direct effects of chronic stress-induced glucocorticoids on various uterine functions and their underlying molecular mechanisms are complex and have not yet been revealed. Recent studies have found that resident stem cell deficiency is responsible for the limited regenerative potential of the endometrium (the innermost lining of the uterine cavity) during each menstrual cycle, which subsequently increases infertility rates. In this context, we hypothesized that stress-induced glucocorticoids directly damage endometrial stem cells and consequently negatively affect endometrial reconstruction, which is important for uterine receptivity. In addition to its well-known canonical roles, we identified for the first time that cortisol, the most abundant and potent glucocorticoid in humans, directly suppresses the multiple beneficial functions (self-renewal, transdifferentiation, and migratory potential) of human endometrial stem cells through its functional receptor, glucocorticoid receptor (GR). Glucocorticoids inhibit well-known survival signals, such as the PI3K/Akt and FAK/ERK1/2 pathways. More importantly, we also found that immobilization of stress-induced glucocorticoids suppresses the various beneficial functions of tissue resident stem cells in vivo. To the best of our knowledge, this is the first study to investigate the direct effects of glucocorticoids on the regenerative capacity of endometrial stem cells, and the findings will facilitate the development of more promising therapeutic approaches to increase female fertility.
慢性应激对许多与生育相关的功能都有负面影响；因此，女性生育力的近期下降似乎至少部分与应激增加有关。糖皮质激素的分泌是对慢性应激的典型内分泌反应，通过下丘脑-垂体-性腺 (HPG) 轴间接降低子宫容受性。然而，除了其众所周知的经典作用外，慢性应激诱导的糖皮质激素对各种子宫功能的直接影响及其潜在的分子机制非常复杂，尚未被揭示。最近的研究发现，驻留干细胞缺乏是导致子宫内膜（子宫腔的最内层）在每个月经周期中有限的再生潜能的原因，这随后增加了不孕率。在这种情况下，我们假设应激诱导的糖皮质激素直接损伤子宫内膜干细胞，从而对子宫内膜重建产生负面影响，而子宫内膜重建对子宫容受性很重要。除了其众所周知的经典作用外，我们首次发现，皮质醇，即人类中最丰富和最有效的糖皮质激素，通过其功能性受体糖皮质激素受体 (GR)，直接抑制人子宫内膜干细胞的多种有益功能（自我更新、转分化和迁移潜能）。糖皮质激素抑制了众所周知的生存信号，如 PI3K/Akt 和 FAK/ERK1/2 通路。更重要的是，我们还发现，应激诱导的糖皮质激素的固定化抑制了体内组织驻留干细胞的各种有益功能。据我们所知，这是第一项研究糖皮质激素对子宫内膜干细胞再生能力的直接影响的研究，研究结果将有助于开发更有前途的治疗方法来提高女性生育力。
