Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling

Paolo Cadinu, Kisha N. Sivanathan, Aditya Misra, Vijay K. Kuchroo, Jeffrey R. Moffitt, Roni Nowarski.


  • MERFISH reveals cellular and spatial remodeling during intestinal inflammation
  • Inflammation-associated fibroblast response is more diverse than expected
  • Neighborhoods define distinct cellular collections that evolve toward ulceration
  • Hallmarks of inflammatory fibroblast states are found in human ulcerative colitis

Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues.