Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells
Abstract 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 u...
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doaj-5b15b85f4e294414ba7205b7cc93928f2021-06-13T11:05:57ZengNature Publishing GroupCell Death and Disease2041-48892021-06-0112611310.1038/s41419-021-03893-4Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cellsSe-Ra Park0Seong-Kwan Kim1Soo-Rim Kim2Doojin Kim3Kun-Woo Kim4In-Sun Hong5Hwa-Yong Lee6Department of Health Sciences and Technology, GAIHST, Gachon UniversityDepartment of Health Sciences and Technology, GAIHST, Gachon UniversityDepartment of Health Sciences and Technology, GAIHST, Gachon UniversityDepartment of Surgery, Gachon University Gil Medical Center, Gachon University School of MedicineDepartment of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical CenterDepartment of Health Sciences and Technology, GAIHST, Gachon UniversityDepartment of Biomedical Science, Jungwon UniversityAbstract 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.https://doi.org/10.1038/s41419-021-03893-4 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Se-Ra Park Seong-Kwan Kim Soo-Rim Kim Doojin Kim Kun-Woo Kim In-Sun Hong Hwa-Yong Lee |
spellingShingle |
Se-Ra Park Seong-Kwan Kim Soo-Rim Kim Doojin Kim Kun-Woo Kim In-Sun Hong Hwa-Yong Lee Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells Cell Death and Disease |
author_facet |
Se-Ra Park Seong-Kwan Kim Soo-Rim Kim Doojin Kim Kun-Woo Kim In-Sun Hong Hwa-Yong Lee |
author_sort |
Se-Ra Park |
title |
Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells |
title_short |
Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells |
title_full |
Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells |
title_fullStr |
Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells |
title_full_unstemmed |
Noncanonical functions of glucocorticoids: A novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells |
title_sort |
noncanonical functions of glucocorticoids: a novel role for glucocorticoids in performing multiple beneficial functions in endometrial stem cells |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-06-01 |
description |
Abstract 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. |
url |
https://doi.org/10.1038/s41419-021-03893-4 |
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