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Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis.

ABSTRACT: Implantation of the fertilized egg depends on the coordinated interplay of cells and molecules that prepare the uterus for this important event. In particular, regulatory T cells (Tregs) are key regulators as their ablation hinders implantation by rendering the uterus hostile for the embryo. In addition, the adoptive transfer of Tregs can avoid early abortion in mouse models. However, it is still not defined which mechanisms underlie Treg function during this early period. Cells of the innate immune system have been reported to support implantation, in part by promoting angiogenesis. In particular, uterine mast cells (uMCs) emerge as novel players at the fetal-maternal interface. Here, we studied whether the positive action of Tregs is based on the expansion of uMCs and the promotion of angiogenesis. We observed that abortion-prone mice have insufficient numbers of uMCs that could be corrected by the adoptive transfer of Tregs. This in turn positively influenced the remodeling of spiral arteries and placenta development as well as the levels of soluble fms-like tyrosine kinase 1 (sFlt-1). Our data suggest an interplay between Tregs and uMCs that is relevant for the changes required at the feto-maternal interface for the normal development of pregnancy.

SUBMITTER: Woidacki K

PROVIDER: S-EPMC4565045 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis.

Woidacki Katja K Meyer Nicole N Schumacher Anne A Goldschmidt Alexandra A Maurer Marcus M Zenclussen Ana Claudia AC

Scientific reports 20150910

Implantation of the fertilized egg depends on the coordinated interplay of cells and molecules that prepare the uterus for this important event. In particular, regulatory T cells (Tregs) are key regulators as their ablation hinders implantation by rendering the uterus hostile for the embryo. In addition, the adoptive transfer of Tregs can avoid early abortion in mouse models. However, it is still not defined which mechanisms underlie Treg function during this early period. Cells of the innate im ...[more]

PMID: 26355667

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Project description:The embryo transfer depth may affect the chance of pregnancy. However, embryo dislodging caused by uterine contraction may occur after the transfer. The aim of the retrospective study was to investigate whether the factors associated with uterine contractilities, such as endometrial thickness and progesterone elevation, affect the association between transfer depth and implantation. A total of 7849 fresh transfer cycles on conventional stimulation in a single in vitro fertilization (IVF) center during the period 2013-2015 was reviewed. Patients were categorized according to quartiles of embryo transfer depth (≤ 9 mm, n = 1735, 9.1-11 mm, n = 2557, 11.1-14 mm, n = 1933, ≥ 1.4 mm, n = 1624, respectively). Adjusted for confounding factors, the adjusted odds ratio (aOR) (95% confidence interval, CI) for clinical pregnancy was 0.90 (0.79-1.02), 0.86 (0.74-0.99), and 0.70 (0.60-0.82) respectively in quartiles 2 through 4, comparing with quartile 1. However, the aORs were significantly increased when the endometrial thickness was < 8 mm. In comparison with that in the cycles with a normal endometrial thickness (8-11 mm), the aORs comparing quartiles 2 through 4 with quartile 1 in the cycles with an endometrial thickness < 8 mm increased from 0.78 (95% CI 0.65-0.93), 0.79 (95% CI 0.65-0.97), and 0.64 (95% CI 0.51-0.81) to 1.73 (95% CI 1.21-2.47), 1.04 (95% CI 0.69-1.56), and 1.45 (95% CI 0.91-2.31), respectively. In the cycles with elevated progesterone and blastocyst stage transfer, the aORs comparing quartiles 4 with quartile 1 decreased from 0.73 (95% CI 0.62-0.87) and 0.74 (95% CI 0.63-0.87) to 0.58 (95% CI 0.40-0.84) and 0.42 (95% CI 0.25-0.73) than those in the cycles without. However, only blastocyst transfer showed a significant interaction with transfer depth (p = 0.043). Our data suggested that endometrial thickness and blastocyst transfer significantly affect the association between embryo transfer depth and clinical pregnancy.

Project description:BackgroundIn the non-pregnant dog, ovarian cyclicity is independent of a uterine luteolysin. This is in contrast to pregnant animals where a prepartum increase of luteolytic PGF2α occurs, apparently originating in the pregnant uterus. Recently, the placenta as a source of prepartum prostaglandins (PGs) was investigated, indicating fetal trophoblast cells as the likely main source. However, the possible contribution of uterine interplacental tissues to the production of these hormones has not yet been thoroughly examined in the dog.MethodsSeveral key factors involved in the production and/or actions of PGs were studied: cyclooxygenase 2 (COX2, PTGS2), PGF2α-synthase (PGFS/AKR1C3), PGE2-synthase (PGES), and the respective receptors FP (PTGFR), EP2 (PTGER2) and EP4 (PGTER4), 15-hydroxyprostaglandin dehydrogenase (HPGD), PG-transporter (PGT, SLCO2A1) and progesterone receptor. Their expression and localization patterns were assessed by Real Time PCR and immunohistology in the interplacental uterine sites from pregnant dogs during the pre-implantation period (days 8-12), post-implantation (days 18-25), mid-gestation (days 35-40) and during antigestagen-induced luteolysis/abortion.ResultsWhereas only low COX2 expression was observed in uterine samples at all the selected time points, expression of PGFS/AKR1C3 strongly increased post-implantation. A gradual increase in PGES-mRNA expression was noted towards mid-gestation. FP-mRNA expression decreased significantly with the progression of pregnancy until mid-gestation. This was associated with clearly detectable expression of HPGD, which did not change significantly over time. The expression of FP and EP2-mRNA decreased significantly over time while EP4-mRNA expression remained unaffected. The antigestagen-treatment led to a significant increase in expression of COX2, PGES, EP2 and PGT (SLCO2A1) mRNA. COX2 was localized predominantly in the myometrium. The expression of PGFS/AKR1C3, which was unchanged, was localized mostly to the surface luminal epithelium. The expression of EP4, PGT and HPGH did not change during treatment, they were co-localized with PGES and EP2 in all uterine compartments.ConclusionsThe data clearly demonstrate the basic capability of the canine pregnant uterus to produce and respond to PGs and suggests their functions both as local regulatory factors involved in the establishment and maintenance of pregnancy, as well as potential contributors to the process of parturition, supporting the myometrial contractility associated with fetal expulsion.

Dataset Information

Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis.

Publications

Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis.

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