During early human pregnancy, the fetal placenta implants into the uterine mucosa (decidua)where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblastdecidual interactions underlie common diseases of pregnancy including pre-eclampsia and stillbirth. Here, we profile transcriptomes of ~70,000 single cells from first trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals new subsets of perivascular and stromal cells, which are located in distinct decidual layers.There are three major subsets of decidual NK cells, with distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes (https://cellphonedb.org/) and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. This identifies many regulatory interactions that prevent any damaging innate or adaptive immune responses in this environment. Our single cell atlas of the maternal-fetal interface reveals the cellular organization and interactions critical for placentation and reproductive success.During early pregnancy, the uterine mucosal lining, the endometrium, is transformed into decidua under the influence of progesterone. Decidualisation results from a complex and well-orchestrated differentiation program that involves all cellular elements of the mucosa: stromal, glandular, and immune cells, including the distinctive decidual Natural Killer cells (dNK) 1,2 . The blastocyst implants into the decidua and initially, before arterial connections are established, uterine glands are the source of histotrophic nutrition in the placenta 3,4 . Following implantation, placental extravillous trophoblast cells (EVT) invade through the decidua and move towards the spiral arteries, where they destroy the smooth muscle media and transform the arteries into high conductance vessels 5 . Balanced regulation of EVT invasion is critical to pregnancy success: arteries must be sufficiently transformed, but excessive invasion prevented, to ensure correct allocation of resources to both mother and baby 6 . The pivotal regulatory role of the decidua is obvious from the life-threatening, uncontrolled, trophoblast invasion that occurs when the decidua is absent as when the placenta implants on a previous cesarean section scar 7 .EVT have a unique HLA profile: they do not express the dominant T cell ligands, class I HLA-A and HLA-B or class II molecules 8,9 , but do express HLA-G and HLA-E and polymorphic HLA-C class I molecules. These trophoblast HLA ligands have receptors expressed by the dominant decidual immune cells, dNK, including maternal killer immunoglobulin-like receptors (KIR), that bind HLA-C molecules 10,11 . Certain combinations of maternal KIR and fetal HLA-C genetic variants are associated with pregnancy disorders such as pre-eclampsia, where trophoblast invasion is deficient 12 . However, detailed understanding of the cellular interactions in the decidua supporting early...

SummaryEmbryonic stem cell (ESC) culture conditions are important for maintaining long-term self-renewal, and they influence cellular pluripotency state. Here, we report single cell RNA-sequencing of mESCs cultured in three different conditions: serum, 2i, and the alternative ground state a2i. We find that the cellular transcriptomes of cells grown in these conditions are distinct, with 2i being the most similar to blastocyst cells and including a subpopulation resembling the two-cell embryo state. Overall levels of intercellular gene expression heterogeneity are comparable across the three conditions. However, this masks variable expression of pluripotency genes in serum cells and homogeneous expression in 2i and a2i cells. Additionally, genes related to the cell cycle are more variably expressed in the 2i and a2i conditions. Mining of our dataset for correlations in gene expression allowed us to identify additional components of the pluripotency network, including Ptma and Zfp640, illustrating its value as a resource for future discovery.

Summary As the first line of defence against pathogens, cells mount an innate immune response, which is highly variable from cell to cell. The response must be potent yet carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here, we characterise this programme’s transcriptional divergence between species and expression variability across cells. Using bulk and single-cell transcriptomics in fibroblasts and mononuclear phagocytes from different species, challenged with immune stimuli, we reveal a striking architecture of the innate immune response. Transcriptionally diverging genes, including cytokines and chemokines, vary across cells and have distinct promoter structures. Conversely, genes involved in response regulation, such as transcription factors and kinases, are conserved between species and display low cell-to-cell expression variability. We suggest that this unique expression pattern, observed across species and conditions, has evolved as a mechanism for fine-tuned regulation, achieving an effective but balanced response.

A number of studies showed that the development and the lifespan of Caenorhabditis elegans is dependent on mitochondrial function. In this study, we addressed the role of mitochondrial DNA levels and mtDNA maintenance in development of C. elegans by analyzing deletion mutants for mitochondrial polymerase gamma (polg-1(ok1548)). Surprisingly, even though previous studies in other model organisms showed necessity of polymerase gamma for embryonic development, homozygous polg-1(ok1548) mutants had normal development and reached adulthood without any morphological defects. However, polg-1 deficient animals have a seriously compromised gonadal function as a result of severe mitochondrial depletion, leading to sterility and shortened lifespan. Our results indicate that the gonad is the primary site of mtDNA replication, whilst the mtDNA of adult somatic tissues mainly stems from the developing embryo. Furthermore, we show that the mtDNA copy number shows great plasticity as it can be almost tripled as a response to the environmental stimuli. Finally, we show that the mtDNA copy number is an essential limiting factor for the worm development and therefore, a number of mechanisms set to maintain mtDNA levels exist, ensuring a normal development of C. elegans even in the absence of the mitochondrial replicase.