Abstract
The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. Here, we use spatial transcriptomics to define how the transcriptomic landscape is spatially organized in the steady state and healing murine colon. At steady state conditions, we demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. Here, we identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. Furthermore, we showed that decreased p53 activation defined areas with increased presence of proliferating epithelial stem cells. Finally, we mapped transcriptomics modules associated with human diseases demonstrating the translational potential of our dataset. Overall, we provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses.
Highlights
The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures
We deconvolved the spatial transcriptomic dataset using non-negative matrix factorization (NNMF) to infer activity maps[12], and we restricted the analysis to only 3 factors that capture the most basic structure of the colon at steady state conditions (d0) (Fig. 1b)
We identified 3 basic structural transcriptomic landscapes that were histologically discernible as intestinal epithelial cells (IEC) (NNMF_3), a mixture between lamina propria (LP) and IEC (NNMF_2), and muscle (NNMF_1), which were indistinguishable from the IEC towards the most distal colon (Fig. 1b)
Summary
The intestinal barrier is composed of a complex cell network defining highly compartmentalized and specialized structures. We demonstrate a previously unappreciated molecular regionalization of the colon, which dramatically changes during mucosal healing. We identified spatially-organized transcriptional programs defining compartmentalized mucosal healing, and regions with dominant wired pathways. We provide a publicly available resource defining principles of transcriptomic regionalization of the colon during mucosal healing and a framework to develop and progress further hypotheses. The intestinal barrier must quickly adapt to promote tissue regeneration and healing following injury. The intestine offers a unique opportunity to investigate common principles of tissue repair at the barrier because of its spatial organization, which is fundamental to its function. Immune, epithelial and stromal cells must quickly adapt within a defined microenvironment and establish a molecular network to promote tissue repair. Targeted technologies for spatial gene expression analysis (e.g. in situ RNA-sequencing, fluorescence in situ hybridization [FISH], RNA-scope) require knowledge of specific candidate genes to interrogate and do not allow an unsupervised investigation of pathways enriched in healing areas
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