Reprogramming roadmap reveals route to human induced trophoblast stem cells.

The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development1-6. The molecular mechanism that underpins these reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas7. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.

Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia.

BACKGROUND: Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce. METHODS: To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation. RESULTS: We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis. CONCLUSIONS: This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.

Can single-cell and spatial omics unravel the pathophysiology of pre-eclampsia?

Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Characterised by the onset of hypertension and proteinuria in the second half of pregnancy, it can lead to maternal end-organ injury such as cerebral ischemia and oedema, pulmonary oedema and renal failure, and potentially fatal outcomes for both mother and fetus. The causes of the different maternal end-organ phenotypes of pre-eclampsia and why some women develop pre-eclampsia condition early in pregnancy have yet to be elucidated. Omics methods include proteomics, genomics, metabolomics, transcriptomics. These omics techniques, previously mostly used on bulk tissue and individually, are increasingly available at a single cellular level and can be combined with each other. Multi-omics techniques on a single-cell or spatial level provide us with a powerful tool to understand the pathophysiology of pre-eclampsia. This review will explore the status of omics methods and how they can and could contribute to understanding the pathophysiology of pre-eclampsia.

CD39 abrogates platelet-derived factors induced IL-1ß expression in the human placenta.

Tissue insults in response to inflammation, hypoxia and ischemia are accompanied by the release of ATP into the extracellular space. There, ATP modulates several pathological processes, including chemotaxis, inflammasome induction and platelet activation. ATP hydrolysis is significantly enhanced in human pregnancy, suggesting that increased conversion of extracellular ATP is an important anti-inflammatory process in preventing exaggerated inflammation, platelet activation and hemostasis in gestation. Extracellular ATP is converted into AMP, and subsequently into adenosine by the two major nucleotide-metabolizing enzymes CD39 and CD73. Here, we aimed to elucidate developmental changes of placental CD39 and CD73 over gestation, compared their expression in placental tissue from patients with preeclampsia and healthy controls, and analyzed their regulation in response to platelet-derived factors and different oxygen conditions in placental explants as well as the trophoblast cell line BeWo. Linear regression analysis showed a significant increase in placental CD39 expression, while at the same time CD73 levels declined at term of pregnancy. Neither maternal smoking during first trimester, fetal sex, maternal age, nor maternal BMI revealed any effects on placental CD39 and CD73 expression. Immunohistochemistry detected both, CD39 and CD73, predominantly in the syncytiotrophoblast layer. Placental CD39 and CD73 expression were significantly increased in pregnancies complicated with preeclampsia, when compared to controls. Cultivation of placental explants under different oxygen conditions had no effect on the ectonucleotidases, whereas presence of platelet releasate from pregnant women led to deregulated CD39 expression. Overexpression of recombinant human CD39 in BeWo cells decreased extracellular ATP levels after culture in presence of platelet-derived factors. Moreover, platelet-derived factors-induced upregulation of the pro-inflammatory cytokine, interleukin-1ß, was abolished by CD39 overexpression. Our study shows that placental CD39 is upregulated in preeclampsia, suggesting an increasing demand for extracellular ATP hydrolysis at the utero-placental interface. Increased placental CD39 in response to platelet-derived factors may lead to enhanced conversion of extracellular ATP levels, which in turn could represent an important anti-coagulant defense mechanism of the placenta.

Effect of Dietary Acetic Acid Supplementation on Plasma Glucose, Lipid Profiles, and Body Mass Index in Human Adults: A Systematic Review and Meta-analysis.

BACKGROUND: Acetic acid is a short-chain fatty acid that has demonstrated biomedical potential as a dietary therapeutic agent for the management of chronic and metabolic illness comorbidities. In human beings, its consumption may improve glucose regulation and insulin sensitivity in individuals with cardiometabolic conditions and type 2 diabetes mellitus. Published clinical trial evidence evaluating its sustained supplementation effects on metabolic outcomes is inconsistent. OBJECTIVE: This systematic review and meta-analysis summarized available evidence on potential therapeutic effects of dietary acetic acid supplementation via consumption of acetic acid-rich beverages and food sources on metabolic and anthropometric outcomes. METHODS: A systematic search was conducted in Medline, Scopus, EMBASE, CINAHL Plus, and Web of Science from database inception until October 2020. Randomized controlled trials conducted in adults evaluating the effect of dietary acetic acid supplementation for a minimum of 1 week were included. Meta-analyses were performed using a random-effects model on fasting blood glucose (FBG), triacylglycerol (TAG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), glycated hemoglobin (HbA1c), body mass index (BMI), and body fat percentage. Statistical heterogeneity was assessed by calculation of Q and I2 statistics, and publication bias was assessed by calculation of Egger's regression asymmetry and Begg's test. RESULTS: Sixteen studies were included, involving 910 participants who consumed between 750 and 3600 mg acetic acid daily in interventions lasting an average of 8 weeks. Dietary acetic acid supplementation resulted in significant reductions in TAG concentrations in overweight and obese but otherwise healthy individuals (mean difference [MD] = -20.51 mg/dL [95% confidence intervals = -32.98, -8.04], P = .001) and people with type 2 diabetes (MD = -7.37 mg/dL [-10.15, -4.59], P < .001). Additionally, acetic acid supplementation significantly reduced FBG levels (MD = -35.73 mg/dL [-63.79, -7.67], P = .01) in subjects with type 2 diabetes compared with placebo and low-dose comparators. No other changes were seen for other metabolic or anthropometric outcomes assessed. Five of the 16 studies did not specify the dose of acetic acid delivered, and no studies measured blood acetate concentrations. Only one study controlled for background acetic acid-rich food consumption during intervention periods. Most studies had an unclear or high risk of bias. CONCLUSION: Supplementation with dietary acetic acid is well tolerated, has no adverse side effects, and has clinical potential to reduce plasma TAG and FBG concentrations in individuals with type 2 diabetes, and to reduce TAG levels in people who are overweight or obese. No significant effects of dietary acetic acid consumption were seen on HbA1c, HDL, or anthropometric markers. High-quality, longer-term studies in larger cohorts are required to confirm whether dietary acetic acid can act as an adjuvant therapeutic agent in metabolic comorbidities management.