SARS-CoV-2-induced disruption of a vascular bed in a microphysiological system caused by type-I interferon from bronchial organoids.

Blood vessels show various COVID-19-related conditions including thrombosis and cytokine propagation. Existing in vitro blood vessel models cannot represent the consequent changes in the vascular structure or determine the initial infection site, making it difficult to evaluate how epithelial and endothelial tissues are damaged. Here, we developed a microphysiological system (MPS) that co-culture the bronchial organoids and the vascular bed to analyze infection site and interactions. In this system, virus-infected organoids caused damage in vascular structure. However, vasculature was not damaged or infected when the virus was directly introduced to vascular bed. The knockout of interferon-related genes and inhibition of the JAK/STAT pathway reduced the vascular damage, indicating the protective effect of interferon response suppression. The results demonstrate selective infection of bronchial epithelial cells and vascular damage by cytokines and also indicate the applicability of MPS to investigate how the infection influences vascular structure and functions.

Three-dimensional tissue model in direct contact with an on-chip vascular bed enabled by removable membranes.

Three-dimensional (3D) tissue culture is a powerful tool for understanding physiological events. However, 3D tissues still have limitations in their size, culture period, and maturity, which are caused by the lack of nutrients and oxygen supply through the vasculature. Here, we propose a new method for culturing a 3D tissue-a spheroid-directly on an 'on-chip vascular bed'. The method can be applied to any 3D tissue because the vascular bed is preformed, so that angiogenic factors from the tissue are not necessary to induce vasculature. The essential component of the assay system is the removable membrane that initially separates the 3D tissue culture well and the microchannel in which a uniform vascular bed is formed, and then allows the tissue to be settled directly onto the vascular bed following its removal. This in vitro system offers a new technique for evaluating the effects of vasculature on 3D tissues.