Uterine DCs are crucial for decidua formation during embryo implantation in mice
Vicki Plaks, Tal Birnberg, Tamara Berkutzki, Shay Sela, Adi BenYashar, Vyacheslav Kalchenko, Gil Mor, Eli Keshet, Nava Dekel, Michal Neeman, Steffen Jung
Vicki Plaks, Tal Birnberg, Tamara Berkutzki, Shay Sela, Adi BenYashar, Vyacheslav Kalchenko, Gil Mor, Eli Keshet, Nava Dekel, Michal Neeman, Steffen Jung
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Research Article

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.

Authors

Vicki Plaks, Tal Birnberg, Tamara Berkutzki, Shay Sela, Adi BenYashar, Vyacheslav Kalchenko, Gil Mor, Eli Keshet, Nava Dekel, Michal Neeman, Steffen Jung

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Figure 8

Evidence for a direct role for uDCs in decidual angiogenesis by regulating vascular maturation.

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Evidence for a direct role for uDCs in decidual angiogenesis by regulati...
(A) Flow cytometry analysis of decidual cells (All) sorted for uNKs and for uDCs. (B) Semiquantitative RT-PCR for sFlt1 of the sorted cells in A. (C) Immunostaining for sFlt1 (brown) of control versus uDC-depleted (DTx) E5.5 ISs. Note that in the control ISs, sFlt1 staining is most abundant in the outer decidual rim, which is the localization of uDCs and also the localization of α-SMA–positive mature vessels (Figure 7H). In uDC-depleted deciduae, the sFlt1 staining is absent. Decidual tissue is circled. (D) Quantification of sFlt1 staining in uDC-depleted IS is shown as percentage of control (DTx: n = 2 mice, n = 3 ISs; control: n = 2 mice, n = 3 ISs; *P = 0.0035). Data quantification was performed on the whole IS (not only the decidua) to avoid bias. (E) Quantifications of sFlt1 distribution in the decidua. Radius of IS center, 240 μm; middle rim, 350 μm; outer rim, 240 μm. Note that the percentage of cells in the outer rim is significantly higher than that in the middle (P = 0.0012) and center (P = 0.0018). (F) Semiquantitative RT-PCR for TGF-β1 of the sorted cells in A. The bands were run on the same gel at the same time but were not contiguous. (G) Semiquantitative RT-PCR for TGF-β1 of uDC-depleted and control IS and (H) quantitative analysis of 3 different experiments. †P < 0.05.