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Dynamic interactions between gut mucosal cells and the external environment are essential to maintain gut homeostasis. Enterochromaffin (EC) cells transduce both chemical and mechanical signals and produce 5-hydroxytryptamine (5-HT) to mediate disparate physiological responses. However, the molecular and cellular basis for functional diversity of ECs remains to be adequately defined. Here, we integrated single-cell transcriptomics with spatial image analysis to identify fourteen EC clusters that are topographically organized along the gut. Subtypes predicted to be sensitive to the chemical environment and mechanical forces were identified that express distinct transcription factors and hormones. A Piezo2+ population in the distal colon was endowed with a distinctive neuronal signature. Using a combination of genetic, chemogenetic and pharmacological approaches, we demonstrated Piezo2+ ECs are required for normal colon motility. Our study constructs a molecular map for ECs and offers a framework for deconvoluting EC cells with pleiotropic functions.
Competing Interest Statement
J.H. and J.W. are paid employees of Takeda Pharmaceuticals.
Footnotes
* 1. Relevant to Fig. 1 and Suppl. Fig 1: Clarified that (i) some GFP is expressed in cells that have not yet fully committed to the EC lineage, or that there is some expression in cells outside this lineage, for example, in mast cells; (ii) it It is possible that the stem cell and transit amplifying cell clusters include cells that are in the process of differentiating into EC cells; and (iii) OSR2 and HOXB13 were preferentially enriched in the ileum and rectum, respectively, in the human samples. 2. Relevant to Fig. 4 and Suppl. Fig. 5: Clarified that our conclusion regarding the presence of subpopulations of EC cells in the proximal colon associated with different physiological roles is based on smFISH data alone. 3. Relevant to Fig. 6: Changed (quote) systematic administration (unquote) to (quote) systemic administration (unquote), (ii) discussed the reason for delayed small intestinal transit in the DTR experiments; (iii) added a comment speculating on why we did not see similar slowing of small intestinal transit in the Villlin-Cre Piezo2 KO; and (iv) added a comment on neural Piezo2 in the discussion, with relevant citations. 4. Throughout the manuscript, we rephrased (quote) nutrient sensing (unquote) to (quote) nutrient sensing and homeostasis (unquote) where appropriate.