This trial demonstrates the technical feasibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety, thereby setting the grounds for adequately powered efficacy studies. (Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure [ESCORT]; NCT02057900).

The outbreak of the Zika Virus (ZIKV) and its association with fetal abnormalities have raised worldwide concern. However, the cellular tropism and the mechanisms of ZIKV transmission to the fetus during early pregnancy are still largely unknown. Therefore, we ex vivo modeled the ZIKV transmission at the maternal-fetal interface using organ culture from first trimester pregnancy samples. Here, we provide evidence that ZIKV strain circulating in Brazil infects and damages tissue architecture of the maternal decidua basalis, the fetal placenta and umbilical cord. We also show that ZIKV replicates differentially in a wide range of maternal and fetal cells, including decidual fibroblasts and macrophages, trophoblasts, Hofbauer cells as well as umbilical cord mesenchymal stem cells. The striking cellular tropism of ZIKV and its cytopathic-induced tissue injury during the first trimester of pregnancy could provide an explanation for the irreversible congenital damages.

Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3–transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3–induced protection from apoptosis. Altogether, our data suggest that the LAG-3–MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3–MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.

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Rationale: Transplantation of allogeneic cardiac stem/progenitor cells (CPC) in experimental myocardial infarction promoted cardiac regeneration and improved heart function. Although this has enhanced prospects of using allogeneic CPC for cardiac repair, the mechanisms regulating the behavior of these allogeneic cells, which are central to clinical applications, remain poorly understood.Objective: T cells orchestrate the allogeneic adaptive immune response. Therefore, to provide insight into the mechanisms regulating the immunologic behavior of human CPC (hCPC), we investigated the allogeneic T-cell response elicited by cryopreserved c-kit-selected hCPC. Methods and Results FoxP3high effector regulatory T cells. The regulatory T-cell proliferation and amplification were dependent on the interaction with the B7 family member programmed death ligand 1 (PD-L1), which is substantially expressed on hCPC and increased under inflammatory conditions. Thus, hCPC in allogeneic settings acquire the capacity to downregulate an ongoing immune response, which was dependent on PD-L1. Conclusions:

Hepatitis E virus (HEV) infection, particularly HEV genotype 1 (HEV-1), can result in fulminant hepatic failure and severe placental diseases, but mechanisms underlying genotype-specific pathogenicity are unclear and appropriate models are lacking. Here, we model HEV-1 infection ex vivo at the maternal-fetal interface using the decidua basalis and fetal placenta, and compare its effects to the less-pathogenic genotype 3 (HEV-3). We demonstrate that HEV-1 replicates more efficiently than HEV-3 both in tissue explants and stromal cells, produces more infectious progeny virions and causes severe tissue alterations. HEV-1 infection dysregulates the secretion of several soluble factors. These alterations to the cytokine microenvironment correlate with viral load and contribute to the tissue damage. Collectively, this study characterizes an ex vivo model for HEV infection and provides insights into HEV-1 pathogenesis during pregnancy that are linked to high viral replication, alteration of the local secretome and induction of tissue injuries.

The natural cytotoxicity receptors NKp46/NCR1, NKp44/NCR2 and NKp30/NCR3 are critical for natural killer (NK) cell functions. Their genes are transcribed into several splice variants whose physiological relevance is not yet fully understood. Here we report that decidua basalis NK (dNK) cells of the pregnant uterine mucosa and peripheral blood NK (pNK) cells, two functionally distinct subsets of the physiological NK cell pool, display differential expression of NKp30/NCR3 and NKp44/NCR2 splice variants. The presence of cytokines that are enriched within the decidual microenvironment is sufficient to convert the splice variant profile of pNK cells into one similar to that of dNK cells. This switch is associated with decreased cytotoxic function and major adaptations to the secretome, hallmarks of the decidual phenotype. Thus, NKp30/NCR3 and NKp44/NCR2 splice variants delineate functionally distinct NK cell subsets. To our knowledge, this is the first conclusive evidence underlining the physiological importance of NCR splice variants.

The recent outbreak of Zika virus (ZIKV) was associated with birth defects and pregnancy loss when maternal infection occurs in early pregnancy, but specific mechanisms driving placental insufficiency and subsequent ZIKV-mediated pathogenesis remain unclear. Here we show, using large scale metabolomics, that ZIKV infection reprograms placental lipidome by impairing the lipogenesis pathways. ZIKV-induced metabolic alterations provide building blocks for lipid droplet biogenesis and intracellular membrane rearrangements to support viral replication. Furthermore, lipidome reprogramming by ZIKV is paralleled by the mitochondrial dysfunction and inflammatory immune imbalance, which contribute to placental damage. In addition, we demonstrate the efficacy of a commercially available inhibitor in limiting ZIKV infection, provides a proof-of-concept for blocking congenital infection by targeting metabolic pathways. Collectively, our study provides mechanistic insights on how ZIKV targets essential hubs of the lipid metabolism that may lead to placental dysfunction and loss of barrier function.