Usp22 is expressed in mouse uterus during early pregnancy and involved in endometrial stromal cell decidualization

Macrophage inhibitory cytokine-1 (MIC-1) is a transforming growth factor-β (TGF-β) superfamily member, first isolated from activated macrophages and subsequently localised in the human placenta. We previously reported that decreased circulating levels in very early pregnancy are associated with subsequent miscarriage. We undertook these current in vitro studies to investigate possible roles for MIC-1 in early pregnancy: (1) regulation of placental matrix metalloproteinase-2 and -9 (MMP-2 and -9); (2) effect on placental apoptosis; and (3) regulation of endometrial stromal cell decidualisation. (1) First trimester placental explant cultures were treated with 100–200 ng/mL MIC-1 � 1/1000 (v/v) anti-MIC-1 antibody. MMP-2 and -9 were measured by gelatin zymography. MMP activation via the plasminogen activation pathway was examined by measuring mRNA expression for urokinase plasminogen activator and its receptor (uPA, uPAR) and type-1 plasminogen activation inhibitor (PAI-1). (2) In first trimester trophoblast explants, apoptosis was induced in vitro with tumor necrosis factor-α (TNF-α) and interferon-β (IFN-β) � 200 ng/mL MIC-1. The pro-apoptosis factor caspase-3 was localised by immunohistochemistry. (3) Using an established model of oestrogen and progesterone induced endometrial stromal cell decidualisation, MIC-1 production was measured and correlated with morphological changes. Cultures were also treated with 20 ng/mL MIC-1. MIC-1 treatment inhibited activation of both MMP-2 and MMP-9 while treatment with anti-MIC-1 antibody blocked the inhibition. uPA, uPAR and PAI-1 mRNA did not change with either treatment. MIC-1 treatment mitigated TNF-α/IFN-β induced trophoblast apoptosis. MIC-1 production increased during induced decidualisation and MIC-1 treatment facilitates further decidualisation in this model. MIC-1 appears to have a number of potentially important functions in the human placenta and decidua consistent with physiological roles in normal placentation. Whether these functions are key to successful pregnancy remains to be studied.

Download Full-text

HOXA10 co-factor MEIS1 is required for the decidualization in human endometrial stromal cell

Journal of Molecular Endocrinology ◽

10.1530/jme-19-0100 ◽

2020 ◽

Vol 64 (4) ◽

pp. 249-258 ◽

Cited By ~ 1

Author(s):

Yawen Xu ◽

Jinhua Lu ◽

Jinxiang Wu ◽

Ruiwei Jiang ◽

Chuanhui Guo ◽

...

Keyword(s):

Stromal Cells ◽

Stromal Cell ◽

Homeobox Gene ◽

Luciferase Reporter ◽

Physical Interaction ◽

Endometrial Stromal Cell ◽

Mouse Uterus ◽

Endometrial Stromal Cells ◽

Human Endometrial Stromal Cell ◽

Decidual Cells

Decidualization is a critical process for embryo implantation and pregnancy maintenance in humans. The homeobox gene HOXA10 has been widely studied in endometrial receptivity establishment and decidualization. MEIS1, a three-amino-acid loop extension (TALE) family homeobox gene, has been proven to be a co-factor for HOXA10 in mouse uterus. However, the interaction between MEIS1 and HOXA10 in the human decidual cells remains to be elucidated. siRNA and CRISPR-Cas9 were employed to knockdown and knockout MEIS1 in the cultured human endometrial stromal cells, and it was found that MEIS1 deficiency leads to impaired decidualization. The physical interaction between the MEIS1 and HOXA10 in human endometrial stromal cell was confirmed by immunoprecipitation. Moreover, KAT2B and ETA were proved to be downregulated in the absence of MEIS1, and luciferase reporter and ChIP assays demonstrated that MEIS1-HOXA10 complex binds to the promoters of KAT2B and ETA and regulates their activity. Overexpression of KAT2B and ETA can partially rescue the decidualization defects in MEIS1-knockout HESCs. Taken together, these data suggest that MEIS1 plays an indispensable role in decidualization in human endometrial stromal cells, and MEIS1 interacts with HOXA10 to regulate the downstream genes, such as KAT2B and ETA. These findings will contribute to our understanding about the regulatory network in the process of decidualization in humans.

Download Full-text

Effect of gonadotropins on human endometrial stromal cell proliferation in vitro

Archives of Gynecology and Obstetrics ◽

10.1007/s00404-002-0292-9 ◽

2002 ◽

Vol 266 (4) ◽

pp. 223-228 ◽

Cited By ~ 25

Author(s):

Seung Yup Ku ◽

Y. M. Choi ◽

Chang Suk Suh ◽

Seok Hyun Kim ◽

Jung Gu Kim ◽

...

Keyword(s):

Cell Proliferation ◽

Stromal Cell ◽

Endometrial Stromal Cell ◽

Human Endometrial Stromal Cell ◽

Proliferation In Vitro

Download Full-text

Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1618433114 ◽

2017 ◽

Vol 114 (6) ◽

pp. E1018-E1026 ◽

Cited By ~ 52

Author(s):

Andrew M. Kelleher ◽

Wang Peng ◽

James K. Pru ◽

Cindy A. Pru ◽

Francesco J. DeMayo ◽

...

Keyword(s):

Stromal Cell ◽

Adult Mouse ◽

Embryo Implantation ◽

Critical Event ◽

Mouse Uterus ◽

Forkhead Box ◽

Uterine Gland ◽

Blastocyst Implantation ◽

Uterine Function ◽

Uterine Glands

Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.

Download Full-text