PRDM14 extinction enables the initiation of trophoblast stem cell formation.

Trophoblast stem cells (TSCs) can be chemically converted from embryonic stem cells (ESCs) in vitro. Although several transcription factors (TFs) have been recognized as essential for TSC formation, it remains unclear how differentiation cues link elimination of stemness with the establishment of TSC identity. Here, we show that PRDM14, a critical pluripotent circuitry component, is reduced during the formation of TSCs. The reduction is further shown to be due to the activation of Wnt/ß-catenin signaling. The extinction of PRDM14 results in the erasure of H3K27me3 marks and chromatin opening in the gene loci of TSC TFs, including GATA3 and TFAP2C, which enables their expression and thus the initiation of the TSC formation process. Accordingly, PRDM14 reduction is proposed here as a critical event that couples elimination of stemness with the initiation of TSC formation. The present study provides novel insights into how induction signals initiate TSC formation.

Prevalence of comorbidity in Chinese patients with COVID-19: systematic review and meta-analysis of risk factors.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease characterized by cough, fever, and fatigue and 20% of cases will develop into severe conditions resulting from acute lung injury with the manifestation of the acute respiratory distress syndrome (ARDS) that accounts for more than 50% of mortality. Currently, it has been reported that some comorbidities are linked with an increased rate of severity and mortality among COVID-19 patients. To assess the role of comorbidity in COVID-19 progression, we performed a systematic review with a meta-analysis on the relationship of COVID-19 severity with 8 different underlying diseases. METHODS: PubMed, Web of Science, and CNKI were searched for articles investigating the prevalence of comorbidities in severe and non-severe COVID-19 patients. A total of 41 studies comprising 12,526 patients were included. RESULTS: Prevalence of some commodities was lower than that in general population such as hypertension (19% vs 23.2%), diabetes (9% vs 10.9%), chronic kidney disease (CKD) (2% vs 9.5%), chronic liver diseases (CLD) (3% vs 24.8%) and chronic obstructive pulmonary disease (COPD) (3% vs 8.6%), while some others including cancer (1% vs 0.6%), cardiovascular disease (6% vs 1.8%) and cerebrovascular disease (2% vs 0.9%) exhibited greater percentage in COVID-19. Cerebrovascular disease (OR = 3.70, 95%CI 2.51-5.45) was found to be the strongest risk factor in disease exacerbation, followed by CKD (OR = 3.60, 95%CI 2.18-5.94), COPD (OR = 3.14, 95% CI 2.35-4.19), cardiovascular disease (OR = 2.76, 95% CI 2.18-3.49), malignancy (OR = 2.63, 95% CI 1.75-3.95), diabetes (OR = 2.49, 95% CI 2.10-2.96) and hypertension (OR = 2.13, 95% CI 1.81-2.51). We found no correlation between CLD and increased disease severity (OR = 1.32, 95% CI 0.96-1.82). CONCLUSION: The impact of all eight underlying diseases on COVID-19 deterioration seemed to be higher in patients outside Hubei. Based on different comorbidities, COVID-19 patients tend to be at risk of developing poor outcomes to a varying degree. Thus, tailored infection prevention and monitoring and treatment strategies targeting these high-risk subgroups might improve prognosis during the COVID-19 pandemic.

Causal Relationship Between Circulating Immune Cells and Recurrent Spontaneous Abortion: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Recurrent spontaneous abortion (RSA) is a serious and common complication of pregnancy caused by multiple factors. The etiology remains incompletely understood, but immunologic factors play important roles. Here, we aimed to evaluate whether circulating immune cells causally impacted RSA. METHODS: In this study, we conducted a comprehensive two-sample Mendelian randomization (MR) study to determine the causal association between the 731 immunophenotypes of human peripheral blood lymphocytes and the number of spontaneous abortions as well as recurrent miscarriage. Sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy. Reverse MR analysis was used to assess reverse causality. RESULTS: After Bonferroni-correction, eight immunophenotypes were significantly associated with the number of spontaneous abortions: FSC-A on CD4+ T cell (beta = -0.051, 95% CI = [-0.085, -0.017], P-value = 0.004), CD8 on HLA DR+ CD8+ T cell (beta = -0.040, 95% CI = [-0.067, -0.014], P-value = 0.003), HLA DR on CD33dim HLA DR+ CD11b- (beta = -0.021, 95% CI = [-0.036, -0.005], P-value = 0.010), HLA DR+ T cell Absolute Count (beta = 0.022, 95% CI = [0.006, 0.037], P-value = 0.008), HLA DR+ T cell % lymphocyte (beta = 0.026, 95% CI = [0.010, 0.041], P-value = 0.001), HLA DR+ T cell % T cell (beta = 0.023, 95% CI = [0.007, 0.039], P-value = 0.004), HLA DR+ CD4+ T cell % lymphocyte (beta = 0.034, 95% CI = [0.007, 0.060], P-value = 0.012), and HLA DR on B cell (beta = 0.012, 95% CI = [0.003, 0.021], P-value = 0.010). In addition, we identified two immunophenotypes associated with recurrent miscarriage: HLA DR on B cell (OR = 0.854, 95% CI = [0.757, 0.964], P-value = 0.011), and CD19 on naive-mature B cell (OR = 4.595, 95% CI = [1.674, 12.617], P-value = 0.003). There was no evidence of heterogeneity, horizontal pleiotropy and reverse causality. CONCLUSIONS: Our study demonstrated a tight link between adaptive immune cells and RSA through genetic means, thus providing potential therapeutic targets or novel diagnostic biomarkers.

The unique expression pattern of human leukocyte antigen in trophoblasts potentially explains the key mechanism of maternal-fetal tolerance and successful pregnancy.

The success of pregnancy mainly depends on immune tolerance of the mother for the semi-allogeneic fetus. The placenta carrying paternal antigens develops in the maternal uterus without suffering immune attack, making the underlying mechanism of maternal tolerance an enduring mystery. As we all know, human leukocyte antigen (HLA) plays an important role in antigen processing and presentation, thus inducing specific immune responses. Therefore, it is reasonable to speculate that the absence of classical HLA class-I（HLA-I) and HLA class-II (HLA-II) molecules in trophoblasts may account for the maternal-fetal tolerance. Here, we review the HLA-involved interactions between trophoblast cells and decidual immune cells, which contribute to the immunotolerance in the development of normal pregnancy. We also compare the similarity between the maternal-fetal interface and tumor-immune microenvironment because the important role of HLA molecules in tumor immune invasion can provide some references to studies of maternal-fetal immune tolerance. Besides, the abnormal HLA expression is likely to be associated with unexplained miscarriage, making HLA molecules potential therapeutic targets. The advances reported by these studies may exert profound influences on other research areas, including tumor immunity, organ transplantation and autoimmune disease in the future.

Macrophage plasticity and function in cancer and pregnancy.

As the soil of life, the composition and shaping process of the immune microenvironment of the uterus is worth exploring. Macrophages, indispensable constituents of the innate immune system, are essential mediators of inflammation and tissue remodeling as well. Recent insights into the heterogeneity of macrophage subpopulations have renewed interest in their functional diversity in both physiological and pathological settings. Macrophages display remarkable plasticity and switch from one phenotype to another. Intrinsic plasticity enables tissue macrophages to perform a variety of functions in response to changing tissue contexts, such as cancer and pregnancy. The remarkable diversity and plasticity make macrophages particularly intriguing cells given their dichotomous role in either attacking or protecting tumors and semi-allogeneic fetuses, which of both are characterized functionally by immunomodulation and neovascularization. Here, we reviewed and compared novel perspectives on macrophage biology of these two settings, including origin, phenotype, differentiation, and essential roles in corresponding microenvironments, as informed by recent studies on the heterogeneity of macrophage identity and function, as well as their mechanisms that might offer opportunities for new therapeutic strategies on malignancy and pregnancy complications.