Endothelial and epithelial cellular barriers play a vital role in the selective transport of solutes and other molecules. The properties and function of these barriers are often affected in case of inflammation and disease. Modelling cellular barriers in vitro can greatly facilitate studies of inflammation, disease mechanisms and progression, and in addition, can be exploited for drug screening and discovery. Here, we report on a parallelizable microfluidic platform in a multiwell plate format with ten independent cell culture chambers to support the modelling of cellular barriers co-cultured with 3D tumor spheroids. The microfluidic platform was fabricated by microinjection molding. Electrodes integrated into the chip in combination with a FT-impedance measurement system enabled transepithelial/transendothelial electrical resistance (TEER) measurements to rapidly assess real-time barrier tightness. The fluidic layout supports the tubeless and parallelized operation of up to ten distinct cultures under continuous unidirectional flow/perfusion. The capabilities of the system were demonstrated with a co-culture of 3D tumor spheroids and cellular barriers showing the growth and interaction of HT29 spheroids with a cellular barrier of MDCK cells.

Background: Pharmacological activation of TREM2 represents a novel therapeutic approach to slow Alzheimer´s disease (AD) progression. Mutations in microglial gene, TREM2, confers increased risk to developing late‐onset AD. Moreover, animal studies demonstrate the loss‐of‐of function variants or complete absence of Trem2 aggravates amyloid pathology. Genetic ablation of TREM2 function has been shown to lock microglia in a homeostatic state, preventing a switch to the disease‐associated state supporting the phagocytic clearance of misfolded proteins and cellular debris. Due to low gene sequence and protein structure homology between mouse and human TREM2, as well as phenotypical disparities between mouse and human microglia, monitoring the impact of TREM2 activation in vivo requires humanized animal models.Method: Here we studied the impact of TREM2 agonism on xenografted human microglia in a mouse model of amyloid pathology. We systematically treated 7‐month‐old transgenic App^NL‐G‐F mice transplanted with human embryonic‐stem‐cell‐derived microglia with TREM2 small molecule agonists. Human microglia were sorted from the brain and subsequently assessed using multi‐omics technologies.Result: The activation of TREM2 lead to increased expression of cytokines and chemokines in xenografted human microglia in the presence of amyloid pathology in App^NL‐G‐F, but not in wild‐type mice. Other changes in the transcriptome profile indicated shifts in microglia populations in TREM2‐agonist‐treated App^NL‐G‐F mice. These effects were observed at exposures consistent with activation of TREM2 in vitro assessed by pSYK and sTREM2 levels.Conclusion: All together, we show the human microglia xenograft mouse model is a valuable tool to study the impact of pharmacological TREM2 activation in the presence of AD neuropathology.