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During human pregnancy, placenta-derived extravillous trophoblasts (EVTs) invade the decidua and commu-nicate with maternal immune cells. The decidua distinguishes into basalis (decB) and parietalis (decP). The latter remains unaffected by EVT invasion. By defining a specific gating strategy, we report the accumulation of macrophages in decB. We describe a decidua basalis-associated macrophage (decBAM) population with a differential transcriptome and secretome compared with decidua parietalis-associated macrophages (dec-PAMs). decBAMs are CD11chi and efficient inducers of Tregs, proliferate in situ, and secrete high levels of CXCL1, CXCL5, M-CSF, and IL-10. In contrast, decPAMs exert a dendritic cell-like, motile phenotype char-acterized by induced expression of HLA class II molecules, enhanced phagocytosis, and the ability to acti-vate T cells. Strikingly, EVT-conditioned media convert decPAMs into a decBAM phenotype. These findings assign distinct macrophage phenotypes to decidual areas depending on placentation and further highlight a critical role for EVTs in the induction of decB-associated macrophage polarization., Funding Agencies|Clinical biomarker facility at SciLifeLab Sweden; Austrian Science Fund [P33485]; Austrian National Bank [17613ONB]

After birth the placenta retires from its vital role during pregnancy and is usually discarded as nothing more than biological waste. Nonetheless, just over a decade ago several scientists and researchers, some of whom are the founders of the International Placenta Stem Cell Society (IPLASS), had the notion that, placental tissues (including amniotic membrane, chorion, cord tissue), could potentially harbor cells with stem cell properties and therapeutic potential. Since then, scientific research has significantly progressed. Not only we are beginning to understand the mechanisms through which placental cells and their derived factors exert their therapeutic actions in different preclinical models, but we are also investigating their safety and efficacy in different clinical trials.