A cellular atlas of intestinal inflammation

PPatients with inflammatory bowel disease (IBD) suffer from symptoms such as abdominal pain, diarrhea, rectal bleeding, and weight loss. As these conditions progress, the cellular environment in the intestine changes dramatically. However, scientists know little about the cellular geography of this remodeling as the disease progresses.

To spatially map the trajectories of cells in the intestine, a team of researchers led by single-cell biologists Jeffrey Moffitt Immunologist at Boston Children’s Hospital Roni Nowalski Researchers at Brigham and Women’s Hospital imaged RNA molecules in intestinal cells before, during, and after inflammation in a mouse model of colitis. cellThe team showed that spatial changes in the intestine occur gradually as the disease progresses and are in part shaped by the presence and distribution of diverse subpopulations of inflammation-associated fibroblasts.¹ Several weeks after removal of the colitis-inducing drug, some of these fibroblasts retained a memory of inflammation.

“Spatial context is important in biology.” Kylie James“Traditionally, this information has been lost,” she explained, because researchers have often analysed these cells after removing them from tissue. previous the study They used spatial transcriptomics to map cellular signatures within the intestinal tract. “One of the unique things here is that we’re also looking at the entire inflammatory trajectory, [at] “You need to look at multiple time points to understand how the cellular signatures change,” James said.^2,3

In this study, the researchers used a spatial transcriptomics technique, multiplex error-robust fluorescence in situ hybridization (MERFISH), to track the trajectory of gene expression during disease progression. They mapped 940 genes in the colons of mice before colitis-inducing drug administration (day 0), early in the disease (day 3), at peak inflammation (day 9), and after recovery (days 21 and 35).

Using these data, the researchers identified 25 tissue neighborhoods that were statistically defined by repeated local cell populations. Each neighborhood consisted of a unique mix of different cell types in specific proportions, including epithelial cells, endothelial cells, immune cells, and fibroblasts. Some neighborhoods were present at all stages (e.g., health and disease), while others were only present at certain time points.

The researchers found that as the disease progressed, the prevalence of many regions changed. Healthy regions declined and inflamed regions emerged. One feature found in most of these diseased regions was the presence of diverse subpopulations of inflammation-associated fibroblasts that arose from healthy fibroblasts. Fibroblasts are important immune regulators, multiple the study Previously, it has been suggested that there is some degree of heterogeneity among inflammatory fibroblasts in IBD.^4,5 In this study, we identified inflammation-associated fibroblast subpopulations that differed in gene expression, spatial location, and emerging disease stage.

“At a functional level, we still don’t really understand what the different subsets of fibroblasts do,” Nowalski says, “and what this study shows is that there’s diversity among fibroblast subsets that we haven’t recognized.”

Some of these fibroblast populations retained inflammatory markers even weeks after the colitis had resolved, suggesting a possible memory of the disease. “This is really intriguing, because in the human setting, we see that people [IBD] “Even after remission, your gut will be different than a healthy person’s,” James says. For example, many patients may experience intermittent and unpredictable symptoms. recurrence.⁶ The time information [presented in this study] It can help us understand IBD even in the absence of active inflammation.”

By examining human data published by other groups, Moffitt, Nowalski and their colleagues found human homologs of many molecular markers of the inflammatory state in fibroblast subpopulations from patients with ulcerative colitis, suggesting that the inflamed human colon may also contain diverse fibroblast subsets associated with inflammation, undergoing changes similar to those reported in this study.

But the authors emphasized that fibroblasts are not the only cells that are changing: “We see almost every cell type responding to the disease,” a co-author said. Paolo Cadine Researchers from Boston Children’s Hospital and Harvard Medical School announced this. This may seem like a trivial conclusion, but “at the same time, [it] This is also very powerful because it suggests that future research should look into the details rather than simply focusing on the how. [a few cell types] They are contributing to the disease.”