Massively multiplexed sequencing of RNA in individual cells is transforming basic and clinical life sciences. However, in standard experiments, tissues must first be dissociated. Thus, after sequencing, information about the spatial relationships between cells is lost although this knowledge is crucial for understanding cellular and tissue-level function. Recent attempts to overcome this fundamental challenge rely on employing additional in situ gene expression imaging data which can guide spatial mapping of sequenced cells. Here we present a conceptually different approach that allows to reconstruct spatial positions of cells in a variety of tissues without using reference imaging data. We first show for several complex biological systems that distances of single cells in expression space monotonically increase with their physical distances across tissues. We therefore seek to map cells to tissue space such that this principle is optimally preserved, while matching existing imaging data when available. We show that this optimization problem can be cast as a generalized optimal transport problem and solved efficiently. We apply our approach successfully to reconstruct the mammalian liver and intestinal epithelium as well as fly and zebrafish embryos. Our results demonstrate a simple spatial expression organization principle and that this principle (or future refined principles) can be used to infer, for individual cells, meaningful spatial position probabilities from the sequencing data alone.
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