Scientists from the Wellcome Sanger Institute, the Universities of Cambridge and Newcastle, and their collaborators have mapped fibroblasts, the body’s scaffolding cells, showing for the first time how they go rogue in diseases affecting multiple organs from acne and psoriasis to rheumatoid arthritis and inflammatory bowel disease.
The findings, published in Nature Immunology, reveal how fibroblasts form distinct “tissue neighbourhoods” and share disease-related functions across organs, suggesting potential universal drug targets.
Using single-cell sequencing, spatial genomics, and machine learning, the researchers identified eight fibroblast types in human skin and observed their distribution in 23 skin disorders, including psoriasis, lupus, and acne.
“We use single-cell resolution spatial transcriptomics to identify high-resolution molecular profiles of fibroblast cells, allowing us to resolve different subtypes and determine their spatial location in human skin,” Lloyd Steele, a researcher at the Wellcome Sanger Institute and University of Cambridge and first author on the paper, told DDN. “The breadth of diseases profiled in skin (e.g., eczema, acne, melanoma, Lyme disease) also allowed us to investigate stromal changes across different settings and identify novel disease-specific markers with a risk of scarring such as acne.”
The researchers then compared fibroblast patterns across other organs, including the endometrium, gut, and lung, in 14 diseases such as inflammatory bowel disease and lung cancer. Machine learning models identified three rogue fibroblast subtypes recurring across different tissues.
“Fibroblasts have been traditionally hard to study due to a lack of reliable surface markers,” said Steele. “Through dissecting the heterogeneity of fibroblast subtypes and identifying ‘rogue’ disease-specific fibroblasts in diseases with scarring risk, before establishing scarring, we identify a potential target for anti-fibrotic therapies. This population can be identified in other tissues, suggesting broader applications.”
The discovery offers a foundation for developing new therapeutics targeting shared disease mechanisms. Still, Steele noted that “drug discovery targeting fibroblasts specifically remains a nascent field. The first approach will likely be targeting fibroblasts in cancer, which appear to modulate immune responses in immunotherapy treatment.” Steele added this approach could also help provide a proof-of-principle for fibroblast-based therapeutics and allow scientists to evaluate possible adverse effects from the drugs.
Steele also emphasized that the integration of artificial intelligence (AI) and spatial genomics was key to these discoveries. “Spatial genomics contextualizes high-resolution cell profiles in space, revolutionizing how we view diseased tissue,” he said. “AI allows us to leverage knowledge from the millions of cells profiled in human tissues already to understand even rare diseases at high resolution.” Looking ahead, he added, “The immediate next step would appear to be modulating cancer-associated fibroblasts in patients who do not respond to immunotherapy. Longer-term, there is a major clinical need for anti-fibrotic treatments, and further understanding mapping regenerative healing and scarring processes in space and time will help us understand this process and develop new therapeutics.”
In a press release, senior author Mo Lotfollahi added that, “Artificial Intelligence is going to be transformative in how we do science in the next 10 years, and guide how we explore vast datasets and make sense of complexities of the human body.”
