A versatile pipeline for the multi-scale digital reconstruction and quantitative analysis of 3 D tissue

14 A prerequisite for the systems biology analysis of tissues is an accurate digital 3D 15 reconstruction of tissue structure based on images of markers covering multiple scales. 16 Here, we designed a flexible pipeline for the multi-scale reconstruction and quantitative 17 morphological analysis of tissue architecture from microscopy images. Our pipeline includes 18 newly developed algorithms that address specific challenges of thick dense tissue 19 reconstruction. Our implementation allows for a flexible workflow, scalable to high20 throughput analysis and applicable to various mammalian tissues. We applied it to the 21 analysis of liver tissue and extracted quantitative parameters of sinusoids, bile canaliculi and 22 cell shapes, recognizing different liver cell types with high accuracy. Using our platform, we 23 uncovered an unexpected zonation pattern of hepatocytes with different size, nuclei and 24 DNA content, thus revealing new features of liver tissue organization. The pipeline also 25 proved effective to analyse lung and kidney tissue, demonstrating its generality and 26 robustness. 27

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