Human BBB-on-a-chip reveals barrier disruption, endothelial inflammation, and T cell migration under neuroinflammatory conditions

The blood-brain barrier (BBB) is a highly selective barrier that ensures a homeostatic environment for the central nervous system (CNS). BBB dysfunction, inflammation, and immune cell infiltration are hallmarks of many CNS disorders, including multiple sclerosis and stroke. Physiologically relevant human in vitro models of the BBB are essential to improve our understanding of its function in health and disease, identify novel drug targets, and assess potential new therapies. We present a BBB-on-a-chip model comprising human brain microvascular endothelial cells (HBMECs) cultured in a microfluidic platform that allows parallel culture of 40 chips. In each chip, a perfused HBMEC vessel was grown against an extracellular matrix gel in a membrane-free manner. BBBs-on-chips were exposed to varying concentrations of pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and interleukin-1 beta (IL-1β) to mimic inflammation. The effect of the inflammatory conditions was studied by assessing the BBBs-on-chips’ barrier function, cell morphology, and expression of cell adhesion molecules. Primary human T cells were perfused through the lumen of the BBBs-on-chips to study T cell adhesion, extravasation, and migration. Under inflammatory conditions, the BBBs-on-chips showed decreased trans-endothelial electrical resistance (TEER), increased permeability to sodium fluorescein, and aberrant cell morphology in a concentration-dependent manner. Moreover, we observed increased expression of cell adhesion molecules and concomitant monocyte adhesion. T cells extravasated from the inflamed blood vessels and migrated towards a C-X-C Motif Chemokine Ligand 12 (CXCL12) gradient. T cell adhesion was significantly reduced and a trend towards decreased migration was observed in presence of Natalizumab, an antibody drug that blocks very late antigen-4 (VLA-4) and is used in the treatment of multiple sclerosis. In conclusion, we demonstrate a high-throughput microfluidic model of the human BBB that can be used to model neuroinflammation and assess anti-inflammatory and barrier-restoring interventions to fight neurological disorders

Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail

Targeting of promising transmembrane proteins for diagnosis and treatment of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of cancer due to the relatively late diagnosis and the limited therapeutic options. Current treatment regimens mainly comprise the cytotoxic agents gemcitabine and FOLFIRINOX. These compounds have shown limited efficacy and severe side effects, highlighting the necessity for earlier detection and the development of more effective, and better-tolerated treatments. Although targeted therapies are promising for the treatment of several types of cancer, identification of suitable targets for early diagnosis and targeted therapy of PDAC is challenging. Interestingly, several transmembrane proteins are overexpressed in PDAC cells that show low expression in healthy pancreas and may therefore serve as potential targets for treatment and/or diagnostic purposes. In this review we describe the 11 most promising transmembrane proteins, carefully selected after a thorough literature search. Favorable features and potential applications of each target, as well as the results of the preclinical and clinical studies conducted in the past ten years, are discussed in detail