Interleukin 22 Expression During the Implantation Window in the Endometrium of Women with Unexplained Recurrent Pregnancy Loss and Unexplained Infertility Compared to Healthy Parturient Individuals

AbstractBreakdown of the feto-maternal interface in early pregnancy causes miscarriage. The cycling endometrium becomes poised to transition to a pregnant state during the midluteal implantation window, coinciding with differentiation of stromal cells into decidual cells (DC) and emergence of senescent decidual cells (snDC). Emerging evidence suggests that DC engage uterine natural killer cells to eliminate their senescent counterparts, thus enabling formation of a robust decidual matrix in pregnancy. To examine if failure to constrain snDC during the peri-implantation window increases the risk of miscarriage, we reconstructed the decidual pathway at single-cell levelin vitroand demonstrated that, without immune surveillance, secondary senescence rapidly transforms DC into progesterone-resistant cells that abundantly express extracellular matrix remodelling factors. Additional single-cell analysis of midluteal endometrium identifiedDIO2andSCARA5as marker genes of a diverging decidual responsein vivo. Finally, we report a conspicuous link between a pro-senescent decidual response in luteal phase endometrium and recurrent pregnancy loss, suggesting that pre-pregnancy screening and intervention may reduce the burden of miscarriage.

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Expression of interleukin-22 in decidua of patients with early pregnancy and unexplained recurrent pregnancy loss

Journal of Assisted Reproduction and Genetics ◽

10.1007/s10815-015-0481-7 ◽

2015 ◽

Vol 32 (6) ◽

pp. 977-984 ◽

Cited By ~ 11

Author(s):

Candice O’Hern Perfetto ◽

Xiujun Fan ◽

Sabita Dahl ◽

Sacha Krieg ◽

Lynn Marie Westphal ◽

...

Keyword(s):

Early Pregnancy ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Interleukin 22

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Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window

Communications Biology ◽

10.1038/s42003-020-0763-1 ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 18

Author(s):

Emma S. Lucas ◽

Pavle Vrljicak ◽

Joanne Muter ◽

Maria M. Diniz-da-Costa ◽

Paul J. Brighton ◽

...

Keyword(s):

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Implantation Window

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Rapamycin Corrects T Regulatory Cell Depletion and Improves Embryo Implantation and Live Birth Rates in a Murine Model

Reproductive Sciences ◽

10.1177/1933719119828110 ◽

2019 ◽

Vol 26 (12) ◽

pp. 1545-1556 ◽

Cited By ~ 2

Author(s):

Greene Donald Royster ◽

Justine C. Harris ◽

Amanda Nelson ◽

Yessenia Castro ◽

R. Patrick Weitzel ◽

...

Keyword(s):

Murine Model ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Embryo Implantation ◽

Mammalian Target Of Rapamycin ◽

Unexplained Infertility ◽

Implantation Failure ◽

T Regulatory Cell ◽

Recurrent Implantation Failure ◽

Regulatory Cell

There are few treatments for patients with recurrent pregnancy loss (RPL) or recurrent implantation failure (RIF). Women with RPL and unexplained infertility have lower T regulatory cell (Treg) expression when compared to fertile controls. A murine model has been developed with depletion of regulatory T cells (DEREG) after administration of diphtheria toxin (DT), resulting in smaller litter sizes, secondary to embryo implantation failure. Numerous murine studies have shown that adoptive transfer of CD4+CD25+FoxP3+ Tregs from donors improves litter sizes in DEREG mice with depleted Tregs. Our hypothesis is that DEREG mice treated with a single dose of DT will deplete Tregs and subsequently decrease litter sizes and that treatment with rapamycin (sirolimus; Pfizer) during the time of embryo implantation will increase Tregs and restore litter sizes nearly back to normal levels. Syngeneic mating of DEREG mice after depletion of Tregs resulted in smaller litter sizes and this defect was reversed when these DEREG mice were treated with rapamycin at the time of embryo implantation. The importance of Tregs at the time of embryo implantation has been well established and immunotherapy treatments, such as rapamycin (mammalian target of rapamycin inhibitor), may prove to be an effective treatment for patients with RPL, RIF, or unexplained infertility with low Treg.

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