Highlights d iPSC and microfluidic technologies were combined to generate a human BBB-Chip d Flow-induced shear and co-cultures enhance barrier performance d The BBB-Chip exhibits physiologically relevant TEER and can predict CNS penetrance d Personalized BBB-Chips can detect interindividual variability in BBB performance

Inactivating mutations in the thyroid hormone (TH) transporter Monocarboxylate transporter 8 (MCT8) cause severe psychomotor retardation in children. Animal models do not reflect the biology of the human disease. Using patient-specific induced pluripotent stem cells (iPSCs), we generated MCT8-deficient neural cells that showed normal TH-dependent neuronal properties and maturation. However, the blood-brain barrier (BBB) controls TH entry into the brain, and reduced TH availability to neural cells could instead underlie the diseased phenotype. To test potential BBB involvement, we generated an iPSC-based BBB model of MCT8 deficiency, and we found that MCT8 was necessary for polarized influx of the active form of TH across the BBB. We also found that a candidate drug did not appreciably cross the mutant BBB. Our results therefore clarify the underlying physiological basis of this disorder, and they suggest that circumventing the diseased BBB to deliver active TH to the brain could be a viable therapeutic strategy.

The human arterial proteome can be viewed as a complex network whose architectural features vary considerably as a function of anatomic location and the presence or absence of atherosclerosis. The data suggest important reductions in mitochondrial protein abundance in early atherosclerosis and also identify a subset of plasma proteins that are highly predictive of angiographically defined coronary disease.

Objective Innate immune protein C1q plays a dual role in the chronic inflammatory disease of atherosclerosis. Complement activation via C1q exacerbates pathology in the atherosclerotic lesion in later stages of the disease. However, in early stages of disease C1q is protective. We hypothesize that complement-independent activities of C1q are involved in reprogramming macrophage inflammatory polarization. Methods The influence of C1q on macrophage inflammatory responses during clearance of oxLDL was examined. Changes in cytokines at the gene and protein level were measured by quantitative PCR and ELISA assay. Results C1q modulated cytokine expression in Raw264.7 macrophages during ingestion of oxLDL. Levels of proinflammatory cytokines IL-1β and IL-6 were downregulated by C1q, whereas levels of the anti-inflammatory cytokine IL-10 were increased. In addition, data from an NFκB-luciferase gene reporter assay suggest that C1q suppresses activation of NFκB during lipoprotein clearance in macrophages, providing one mechanism by which C1q downregulates pro-inflammatory cytokine production. Conclusions C1q-polarization of macrophages toward an anti-inflammatory (M2-like) phenotype may be important in dampening inflammation in the early atherosclerotic lesion. Further investigation of molecular pathways targeted by C1q may provide novel therapeutic targets for this disease.

Coronary artery disease remains a leading cause of death in industrialized nations, and early detection of disease is a critical intervention target to effectively treat patients and manage risk. Proteomic analysis of mixed tissue homogenates may obscure subtle protein changes that occur uniquely in underlying tissue subtypes. The unsupervised ‘convex analysis of mixtures’ (CAM) tool has previously been shown to effectively segregate cellular subtypes from mixed expression data. In this study, we hypothesized that CAM would identify proteomic information specifically informative to early atherosclerosis lesion involvement that could lead to potential markers of early disease detection. We quantified the proteome of 99 paired abdominal aorta (AA) and left anterior descending coronary artery (LAD) specimens (N = 198 specimens total) acquired during autopsy of young adults free of diagnosed cardiac disease. The CAM tool was then used to segregate protein subsets uniquely associated with different underlying tissue types, yielding markers of normal and fibrous plaque (FP) tissues in LAD and AA (N = 62 lesions markers). CAM-derived FP marker expression was validated against pathologist estimated luminal surface involvement of FP, as well as in an orthogonal cohort of “pure” fibrous plaque, fatty streak, and normal vascular specimens. A targeted mass spectrometry (MS) assay quantified 39 of 62 CAM-FP markers in plasma from women with angiographically verified coronary artery disease (CAD, N = 46) or free from apparent CAD (control, N = 40). Elastic net variable selection with logistic regression reduced this list to 10 proteins capable of classifying CAD status in this cohort with <6% misclassification error, and a mean area under the receiver operating characteristic curve of 0.992 (confidence interval 0.968–0.998) after cross validation. The proteomics-CAM workflow identified lesion-specific molecular biomarker candidates by distilling the most representative molecules from heterogeneous tissue types.