The small and large intestine contain related mesenchymal subsets that derive from embryonic Gli1 + precursors

Simone Isling Pærregaard, Line Wulff, Sophie Schussek, Kristoffer Niss, Urs Mörbe, Johan Jendholm, Kerstin Wendland, Anna T. Andrusaite, Kevin F. Brulois, Robert J.B. Nibbs, Katarzyna Sitnik, Allan Mc I. Mowat, Eugene C. Butcher, Søren Brunak, William W. Agace*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

The intestinal lamina propria contains a diverse network of fibroblasts that provide key support functions to cells within their local environment. Despite this, our understanding of the diversity, location and ontogeny of fibroblasts within and along the length of the intestine remains incomplete. Here we show that the small and large intestinal lamina propria contain similar fibroblast subsets that locate in specific anatomical niches. Nevertheless, we find that the transcriptional profile of similar fibroblast subsets differs markedly between the small intestine and colon suggesting region specific functions. We perform in vivo transplantation and lineage-tracing experiments to demonstrate that adult intestinal fibroblast subsets, smooth muscle cells and pericytes derive from Gli1-expressing precursors present in embryonic day 12.5 intestine. Trajectory analysis of single cell RNA-seq datasets of E12.5 and adult mesenchymal cells suggest that adult smooth muscle cells and fibroblasts derive from distinct embryonic intermediates and that adult fibroblast subsets develop in a linear trajectory from CD81+ fibroblasts. Finally, we provide evidence that colonic subepithelial PDGFRαhi fibroblasts comprise several functionally distinct populations that originate from an Fgfr2-expressing fibroblast intermediate. Our results provide insights into intestinal stromal cell diversity, location, function, and ontogeny, with implications for intestinal development and homeostasis.

Original languageEnglish
Article number2307
JournalNature Communications
Volume14
Issue number1
Number of pages16
ISSN2041-1723
DOIs
Publication statusPublished - 2023

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