3D reconstruction of human liver tissue at cellular resolution

The liver contains an intricate microstructure that is critical for proper liver function. Architectural disruption of this spatial structure is pathologic. Unfortunately, two-dimensional (2D) histopathology-the gold standard for pathological understanding of many liver diseases-can misrepresent or leave gaps in our understanding of complex 3D structural features. Here, we used immunostaining, tissue clearing, microscopy, and computational software to create 3D multilobular reconstructions of both nonfibrotic and cirrhotic human liver tissue. We found that spatial architecture in human cirrhotic liver samples with varying etiologies had sinusoid zonal dysregulation, reduction in glutamine synthetase-expressing pericentral hepatocytes, regression of central vein networks, disruption of hepatic arterial networks, and fragmentation of biliary networks, which together suggest a pro-portalization/decentralization phenotype in cirrhotic tissue. Further implementation of 3D pathological analyses may provide a deeper understanding of cirrhotic pathobiology and inspire treatments for liver disease.