Uterine DCs are crucial for decidua formation during embryo implantation in mice

Abstract

Implantation is a key stage during pregnancy, as the fate of the embryo is often decided upon its first contact with the maternal endometrium. Around this time, DCs accumulate in the uterus; however, their role in pregnancy and, more specifically, implantation, remains unknown. We investigated the function of uterine DCs (uDCs) during implantation using a transgenic mouse model that allows conditional ablation of uDCs in a spatially and temporally regulated manner. Depletion of uDCs resulted in a severe impairment of the implantation process, leading to embryo resorption. Depletion of uDCs also caused embryo resorption in syngeneic and T cell-deficient pregnancies, which argues against a failure to establish immunological tolerance during implantation. Moreover, even in the absence of embryos, experimentally induced deciduae failed to adequately form. Implantation failure was associated with impaired decidual proliferation and differentiation. Dynamic contrast-enhanced MRI revealed perturbed angiogenesis characterized by reduced vascular expansion and attenuated maturation. We suggest therefore that uDCs directly fine-tune decidual angiogenesis by providing two critical factors, sFlt1 and TGF-β1, that promote coordinated blood vessel maturation. Collectively, uDCs appear to govern uterine receptivity, independent of their predicted role in immunological tolerance, by regulating tissue remodeling and angiogenesis. Importantly, our results may aid in understanding the limited implantation success of embryos transferred following in vitro fertilization. IntroductionImplantation is a critical stage in the establishment of pregnancy. Failure of the embryo to implant is clinically relevant to recurrent pregnancy loss and low success of in vitro fertilization. Despite some differences, the general principles of implantation are well conserved among mammalian species (1). Murine implantation starts with blastocyst apposition to the endometrium and attachment (E4-E4.5, vaginal plug is E0.5) that triggers the uterine stroma to proliferate and differentiate into the decidua, a spongy cell mass surrounding the blastocyst. Implantation then continues with the erosion of the epithelium that separates the blastocyst from the stroma, and embryonic trophoblasts invade the decidua and inner myometrium to reach maternal vessels. Decidualization is tightly associated with the spatial and temporal regulation of angiogenesis, i.e., the development of new capillaries from preexisting vessels (2). Angiogenesis at the implantation site (IS) is characterized by localized uterine vascular permeability along with the development of maternal vessels. With time, the latter dramatically increase in number and diameter in order to supply the fetal growing needs for oxygen and metabolites. The decidua supports the pregnancy, sustaining the embryo until the placenta is developed by E10. The decidua basalis, a remnant of the decidua at the implantation chamber will eventually be part of the outer side of the placenta, as it contacts the myometriu...

In vivo visualization of uterine mast cells by two-photon microscopy

“…MCs accumulated at the receptive phase of the female, namely in estrus when the uterine tissue is prepared for the nidation of the blastocyst. A similar distribution pattern could be observed live for DCs which additionally showed a clustering in estrus and are known to be crucial for the implantation process (Plaks et al 2008). The accumulation of MCs at estrus could affect the physical as well as physiological contacts between the blastocyst and the uterine epithelium.…”

Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep

“…The increase in expression of TLR2, TLR7, TLR8, and TLR9 in the endometrium during early pregnancy probably results from both progesterone-dependent recruitment of immune cells enriched in these particular TLRs (Segerson et al 1991, Plaks et al 2008, Gomez-Lopez et al 2010, Mansouri-Attia et al 2012 and changes in uterine gene expression required for pregnancy (Young et al 2004, Jorgenson et al 2005, Aflatoonian et al 2007, Hirata et al 2007, Turner et al 2012. In view of the significant increase in steady-state levels of both TLR7 and TLR8 mRNAs in uteri of early pregnant ewes, we determined cell-specific expression of TLR7 and TLR8 proteins to be particularly abundant in uterine LE and sGE and expressed in a temporal and cell-specific manner that differed due to reproductive TLR and establishment of pregnancy in sheep status, which supports results obtained from previous studies (Jorgenson et al 2005, Aflatoonian et al 2007, Hirata et al 2007.…”

“…However, large numbers of immune cells are recruited into the endometrium during the estrous cycle and pregnancy to participate in events of uterine remodeling, maternal tolerance, vascularization, and placentation (Segerson et al 1991, Leonard et al 2006, Laskarin et al 2007, Gomez-Lopez et al 2010, Nagamatsu & Schust 2010, Mansouri-Attia et al 2012. Lacking this influx of immune cells or their aberrant function leads to infertility and pregnancy loss (Greenwood et al 2000, Plaks et al 2008, Guerin et al 2009, Jabbour et al 2009, Erlebacher 2013. Therefore, it is unlikely that the maternal immune system is suppressed during pregnancy.…”

Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus

“…Dendritic cells (DCs), [49,50] macrophages, [51] and uterine NK [52] cells are all involved in this complex regulation of tolerance. Current evidence suggests that Tregs also play an important role in this phenomenon, both in the periphery as well as locally at the FMI.…”