A Spatially Resolved Molecular Atlas of Human Endothelium

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ABSTRACT - OVERALL We propose to establish the Caltech-UW Tissue Mapping Center (TMC), which will serve as one of the T​MCs of the NIH’s Human BioMolecular Atlas Program (HuBMAP). The overarching goal of the TMCs is to generate high-resolution, high-content multiscale maps of non-diseased human organs and systems. To this end, we propose a TMC that brings together the developers of leading technologies for multiplex spatial transcriptomics (Long Cai, seqFISH) and ultra-scalable methods for single cell profiling of chromatin accessibility and transcriptomes (Shendure & Trapnell, sci-ATAC-seq and sci-RNA-seq). Through an organ specific project (OSP), we describe a pipeline to collect high quality, normal human samples with explicit consent for open access genome data sharing (GDS) and distribution to consortium members. We will characterize and quantify the molecular heterogeneity of the human circulatory system in relation to multiple facets of its anatomical distribution, including organ-specific heterogeneity, intra-organ zonality, down to cell-to-cell heterogeneity. Through an iterative approach involving profiling of spatially intact tissues by seqFISH and disaggregated cells by sci-ATAC-seq and sci-RNA-seq, we will obtain a spatially resolved, comprehensive molecular portrait of both chromatin accessibility and gene expression across the human circulatory system. Through incidental collection, we anticipate generating expression and chromatin accessibility data for diverse cell types in all organs that we survey, which will critically inform and increase the value of the datasets collected by other TMCs and OSPs. We will work closely and openly with the other TMCs and the broader HuBMAP program to share and integrate data as well as methods and ultimately build a broadly useful platform for exploring and understanding human organs and systems at high molecular and anatomical resolution.