| Popis: |
Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels that lack smooth muscle and are partially lined with EVTs instead of vascular endothelium. Several mechanisms have been proposed to explain how EVTs coordinate with decidual cells to promote a tissue microenvironment conducive to spiral artery remodeling (SAR). However, it remains a matter of debate which immune and stromal cell types participate in these interactions, how this process evolves with respect to gestational age, and which anatomic routes are the predominate path of EVT invasion in humans. To elucidate this complex interplay, we used multiplexed ion beam imaging by time of flight with a 37-plex antibody panel to build the first spatio-temporal atlas of the human maternal-fetal interface in the first half of pregnancy at single-cell resolution. We analyzed ~500,000 cells and 588 spiral arteries within intact decidua from 66 patients between 6-20 weeks of gestation. Using custom machine learning algorithms for cell segmentation and classification, we evaluated the spatial distributions and phenotype of 20 maternal and five EVT populations with respect to gestational age and SAR. Gestational age substantially influenced the frequency of most maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, Galectin-9, and IDO-1 preferentially enriched at later time points. In contrast, SAR progression, and not gestational age, preferentially correlated with local invasion of EVTs. Lastly, by comparing spatial co-occurrence and phenotype of decidual interstitial, perivascular and intravascular EVTs with respect to SAR progression, we developed a statistical model suggesting an intravasation mechanism as the predominant route of EVT invasion in superficial decidua. Taken together, these results support a coordinated model of decidualization in which increasing gestational age drives a transition in maternal decidua towards a tolerogenic niche conducive to locally regulated, EVT-dependent SAR. |
