Ureter single-cell and spatial mapping reveal cell types, architecture, and signaling networks

Tissue engineering offers a promising treatment strategy for ureteral strictures. Successful ureter engineering is necessitated by detailed understanding of the tissue architecture, cellular heterogeneity, and signaling pathways underlying regeneration. We define and spatially map cell populations within the human ureter by using a combinatorial approach: single-cell RNA sequencing, 10X Visium spatial transciptomics, and immunofluorescence. The stromal and urothelial cell populations are analyzed in detail, and we infer potential cell-cell communication networks underpinning the bi-directional crosstalk between these compartments. Specifically, we analyze and experimentally validate the importance of Sonic Hedgehog (SHH) signaling pathway in adult stem cell maintenance. The SHH-expressing basal cells support organoid generation in vitro, and accurately predict the differentiation trajectory of basal stem cells, to terminally differentiated umbrella cells, in vivo. Our results highlight essential processes involved in adult ureter tissue homeostasis, and provide a toolkit for guiding ureter tissue engineering. Overall design: Two normal human ureters each were subjected to spatial transcriptomics using 10X Genomics Spatial Gene Expression. Data was processed using Spaceranger 1.3.0 and anayzed using Seurat v4.0.4 to better understand the architecture and cellular heterogeneity of the ureter. These samples have matching single cell RNAseq data, which were used to enhance and validate the Spatial Gene Expression data.

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