RESUMEN
Background: A well-known blood biomarker (soluble fms-like tyrosinase-1 [sFLT-1]) for preeclampsia, i.e., a pregnancy disorder, was found to predict severe COVID-19, including in males. True biomarker may be masked by more-abrupt changes related to endothelial instead of placental dysfunction. This study aimed to identify blood biomarkers that represent maternal-fetal interface tissues for predicting preeclampsia but not COVID-19 infection. Methods: The surrogate transcriptome of tissues was determined by that in maternal blood, utilizing four datasets (n = 1354) which were collected before the COVID-19 pandemic. Applying machine learning, a preeclampsia prediction model was chosen between those using blood transcriptome (differentially expressed genes [DEGs]) and the blood-derived surrogate for tissues. We selected the best predictive model by the area under the receiver operating characteristic (AUROC) using a dataset for developing the model, and well-replicated in datasets both with and without an intervention. To identify eligible blood biomarkers that predicted any-onset preeclampsia from the datasets but that were not positive in the COVID-19 dataset (n = 47), we compared several methods of predictor discovery: (1) the best prediction model; (2) gene sets of standard pipelines; and (3) a validated gene set for predicting any-onset preeclampsia during the pandemic (n = 404). We chose the most predictive biomarkers from the best method with the significantly largest number of discoveries by a permutation test. The biological relevance was justified by exploring and reanalyzing low- and high-level, multiomics information. Results: A prediction model using the surrogates developed for predicting any-onset preeclampsia (AUROC of 0.85, 95 % confidence interval [CI] 0.77 to 0.93) was the only that was well-replicated in an independent dataset with no intervention. No model was well-replicated in datasets with a vitamin D intervention. None of the blood biomarkers with high weights in the best model overlapped with blood DEGs. Blood biomarkers were transcripts of integrin-α5 (ITGA5), interferon regulatory factor-6 (IRF6), and P2X purinoreceptor-7 (P2RX7) from the prediction model, which was the only method that significantly discovered eligible blood biomarkers (n = 3/100 combinations, 3.0 %; P =.036). Most of the predicted events (73.70 %) among any-onset preeclampsia were cluster A as defined by ITGA5 (Z-score ≥ 1.1), but were only a minority (6.34 %) among positives in the COVID-19 dataset. The remaining were predicted events (26.30 %) among any-onset preeclampsia or those among COVID-19 infection (93.66 %) if IRF6 Z-score was ≥-0.73 (clusters B and C), in which none was the predicted events among either late-onset preeclampsia (LOPE) or COVID-19 infection if P2RX7 Z-score was <0.13 (cluster C). Greater proportions of predicted events among LOPE were cluster A (82.85 % vs 70.53 %) compared to early-onset preeclampsia (EOPE). The biological relevance by multiomics information explained the biomarker mechanism, polymicrobial infection in any-onset preeclampsia by ITGA5, viral co-infection in EOPE by ITGA5-IRF6, a shared prediction with COVID-19 infection by ITGA5-IRF6-P2RX7, and non-replicability in datasets with a vitamin D intervention by ITGA5. Conclusions: In a model that predicts preeclampsia but not COVID-19 infection, the important predictors were genes in maternal blood that were not extremely expressed, including the proposed blood biomarkers. The predictive performance and biological relevance should be validated in future experiments.
RESUMEN
The development of a direct reprogramming method to provide cell availability for regenerative therapy has led to a lot of studies. However, the search for appropriate cell sources and methods is still being carried out until now. Direct reprogramming using microRNA-1 (miR-1) is an option to obtain cardiomyocytes from other cells because miR-1 has evidence to play a role in the development of cardiac muscle cells in the embryo. This study aimed to compare the direct reprogramming efficiency of CD34+ cells from peripheral blood into cardiomyocytes between cardiomyocyte differentiation medium and miR-1. CD34+ cells from peripheral blood isolation and expansion process was conducted for 7 days using magnetic-activated cell sorting. Cardiomyocyte differentiation medium added in P1 group and transfection of miR-1 in P2 group of cell culture. Cardiac troponin immunocytochemistry staining and measurement were done on the fifth day after cell culture treatment. Cardiac troponin expression was observed higher in the P2 group (median 31.34) compared to the P1 group (median 21.06) (p = 0.000). The efficiency of direct reprogramming of CD34+ cells into cardiomyocytes with cardiomyocyte differentiation medium was 13%-21% and with miR-1 transfection was 31%-32%. Both the addition of miR-1 and cardiomyocyte differentiation medium could directly reprogram CD34+ cells into cardiomyocytes. The efficiency of miR-1 in reprogramming CD34+ cells into cardiomyocytes is superior to cardiomyocytes differentiation medium.