Microgravity inhibits decidualization via decreasing Akt activity and FOXO3a expression in human endometrial stromal cells

Cho, Hye Jeong; Baek, Mi Ock; Khaliq, Sana Abdul; Chon, Seung Joo; Son, Kuk Hui; Lee, Sung Ho; Yoon, Mee Sup

doi:10.1038/s41598-019-48580-9

Cited by 21 publications

(13 citation statements)

References 38 publications

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“…Several studies investigating the impact of µ g on the behaviour and health of mice on the ISS were published in this Collection 18–23 , in addition to investigations at the cellular level in space 24 and in short-term µ g provided by PF maneuvers 25 . Moreover, cell studies in simulated (s-) µ g at ground-based facilities are included in this Collection 26–30 .…”

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confidence: 99%

“…Cho et al . 30 examined endometrial stroma cells exposed to 3D clinorotation and showed that µ g inhibited decidualisation by reducing forkhead box O3 (FOXO3a) expression, autophagic flux and proliferation, as well as decreasing protein kinase B (Akt) activity, matrix metallopeptidase 2 (MMP2) expression and migration. They suggested that µ g during spaceflight might lead to an unreceptive endometrium by suppressing decidualisation potential 30 .…”

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confidence: 99%

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Guest Edited Collection: Gravitational biology and space medicine

Grimm

2019

Sci Rep

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A return to the Moon, Mars expeditions, and a rise in space tourism will lead to an increasing number of human spaceflights. The ‘Gravitational biology and space medicine’ Collection focuses on the challenges to the health of humans in space during long-term space missions and the physiological changes during short-term altered gravity conditions, the possible influence of space radiation, available countermeasures and possible applications on Earth. In addition, studies reporting on in vivo changes in space-flown mice were published. Finally, this Collection also brings together articles reporting experiments using cells cultured under conditions of real microgravity on the International Space Station, or exposed in ground-based facilities, in order to study morphological and molecular alterations in different cell types.

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confidence: 99%

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confidence: 99%

Guest Edited Collection: Gravitational biology and space medicine

Grimm

2019

Sci Rep

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“…Decidualization is known to facilitate implantation and maintain pregnancy (Cho et al 2019). Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium, which occur at 24:00 h on day 4 of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

Endometrial pyruvate kinase M2 is essential for decidualization during early pregnancy

Guo

Liu

et al. 2020

Journal of Endocrinology

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Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.

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“…A correlation between SKP2 overexpression and elevated AKT1 activity has been reported in many carcinomas [ 20 , 21 ]. Both ERK1/2 and AKT signaling, which mediate gene expression associated with decidualization and glucose uptake, are essential for human endometrial decidualization [ 22 , 23 ]. These results suggest a positive regulatory role of SKP2 in decidualization.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of decidual SKP2 is associated with human recurrent miscarriage

Liu

et al. 2021

Reprod Biol Endocrinol

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Background Recurrent miscarriage (RM) is a very frustrating problem for both couples and clinicians. To date, the etiology of RM remains poorly understood. Decidualization plays a critical role in implantation and the maintenance of pregnancy, and its deficiency is closely correlated with RM. The F-box protein S-phase kinase associated protein 2 (SKP2) is a key component of the SCF-type E3 ubiquitin ligase complex, which is critically involved in ErbB family-induced Akt ubiquitination, aerobic glycolysis and tumorigenesis. SKP2 is pivotal for reproduction, and SKP2-deficient mice show impaired ovarian development and reduced fertility. Methods Here, we investigated the expression and function of SKP2 in human decidualization and its relation with RM. A total of 40 decidual samples were collected. Quantitative PCR analysis, western blot analysis and immunohistochemistry analysis were performed to analyze the differential expression of SKP2 between RM and control cells. For in vitro induction of decidualization, both HESCs (human endometrial stromal cells) cell line and primary ESCs (endometrial stromal cells) were used to analyze the effects of SKP2 on decidualization via siRNA transfection. Results Compared to normal pregnant women, the expression of SKP2 was reduced in the decidual tissues from individuals with RM. After in vitro induction of decidualization, knockdown of SKP2 apparently attenuated the decidualization of HESCs and resulted in the downregulation of HOXA10 and FOXM1, which are essential for normal human decidualization. Moreover, our experiments demonstrated that SKP2 silencing reduced the expression of its downstream target GLUT1. Conclusions Our study indicates a functional role of SKP2 in RM: downregulation of SKP2 in RM leads to impaired decidualization and downregulation of GLUT1 and consequently predisposes individuals to RM.

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Microgravity inhibits decidualization via decreasing Akt activity and FOXO3a expression in human endometrial stromal cells

Cited by 21 publications

References 38 publications

Guest Edited Collection: Gravitational biology and space medicine

Guest Edited Collection: Gravitational biology and space medicine

Endometrial pyruvate kinase M2 is essential for decidualization during early pregnancy

Downregulation of decidual SKP2 is associated with human recurrent miscarriage

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