Unmasking the Culprits: How Different Skin Cells Drive Systemic Sclerosis
Systemic sclerosis (SSc), sometimes called scleroderma, is a complex disease where the body produces too much collagen, leading to a painful hardening and thickening of the skin and sometimes internal organs. At the heart of this process are cells called fibroblasts. Fibroblasts are normally the architects of our tissues, building the structural framework, but in SSc, they become overactive and produce excessive collagen and other proteins, leading to fibrosis (scarring).
Scientists know that fibroblasts are central to SSc, but studying them has been tricky. Standard methods of growing fibroblasts in the lab haven't fully captured the complex ways these cells behave inside the body. This new research, published in JCI Insight by Kristina E.N. Clark and colleagues from University College London and the University of Oxford, aimed to get a clearer picture of different fibroblast types in SSc skin and understand their roles.
Delving into the Skin: Finding Different Fibroblast Types: The researchers took small skin biopsies from people with a type of SSc called diffuse cutaneous SSc (dcSSc) and from healthy volunteers. They used a clever method to separate two main types of fibroblasts based on their behaviour in the lab.
First, they let fibroblasts grow out from the skin biopsy pieces placed in a culture dish. These are the "migratory" fibroblasts, as they are the first to move away from the tissue. After collecting these, they used an enzyme (collagenase) to break down the remaining tissue and isolate the cells that stayed put. These are the "non-migratory" or "resident" fibroblasts.
Peeking Inside: The Power of Gene Sequencing: To understand what these different fibroblast types were doing, the scientists looked at their gene activity using advanced techniques.
They used bulk RNA sequencing to get an overall view of which genes were active in large groups of isolated migratory and resident fibroblasts from both healthy people and those with SSc. They also used single-cell RNA sequencing (scRNAseq), which allowed them to look at the gene activity of thousands of individual cells directly from skin biopsies. This single-cell approach is powerful because it can identify distinct subgroups of cells even within what was previously thought to be a single type.
Using the single-cell data, they created a detailed 'atlas' or map showing different fibroblast populations in the skin. They then used this map to understand where the migratory and resident fibroblasts they isolated fit within the complex mix of cells found in SSc skin.
What Did They Discover? Distinct Roles in SSc Progression: The findings revealed that the different fibroblast types behave differently in SSc skin, and their roles change as the disease progresses.
- Healthy Skin: In healthy skin, the researchers could identify distinct populations, including the migratory and resident types.
- Early-Stage SSc Skin: In people with early SSc, both migratory and resident fibroblasts were found to be activated. This activation phase seems to be influenced by important signalling molecules like TGFβ and CCL2.
- Late-Stage SSc Skin: As SSc progresses, the picture changes significantly. The study found that profibrotic non-migratory ("resident") fibroblasts become the predominant type in late-stage SSc skin. These are the cells most strongly associated with the excessive scarring characteristic of SSc. Like in early SSc, these cells are also influenced by signals such as TGFβ and CCL2.
The bulk RNA sequencing data clearly showed notable differences in gene expression between the SSc migratory and SSc resident fibroblasts, setting them apart. For example, specific genes like CCL2 and CCL19 were found to be more active in resident fibroblasts, while genes like STC2 and COMP were higher in migratory fibroblasts.
Beyond just looking at genes, the researchers also tested the functional abilities of these isolated fibroblasts in the lab. They performed 'scratch assays' to see how well the cells could move to close a gap (simulating wound healing) and tested their ability to contract a collagen gel, which reflects their capacity to pull and stiffen tissue. The results showed differences in these functional properties between the fibroblast types from SSc patients and healthy controls, and also between SSc migratory and resident fibroblasts. For instance, Figure 1 illustrates differences in gap closure and collagen gel contraction between the groups. They also looked at protein levels of markers associated with fibrosis, such as α-smooth muscle actin (αSMA), Connective Tissue Growth Factor (CCN2), and Collagen Type 1 (COL1), finding differences between the fibroblast populations.
Further analysis confirmed that signalling pathways involving TGFβ and CCL are influential in different fibroblast populations in both early and late-stage SSc. They showed that the cultured fibroblasts responded to these molecules.
Why Does This Matter? Towards Smarter Treatments: Identifying a specific pathogenic non-migratory fibroblast population that dominates in late-stage SSc is a significant finding. It suggests that not all fibroblasts are equally involved in driving the disease, and that a particular group is key to the progressive fibrosis.
This understanding could pave the way for more targeted therapies for SSc. Instead of broadly trying to suppress all fibroblast activity (which might have unwanted side effects), future treatments might focus specifically on blocking or altering the behaviour of these problematic non-migratory cells or the signals like TGFβ and CCL that activate them. This could potentially reduce fibrosis more effectively while leaving other necessary fibroblast functions untouched.
Important Considerations: It's worth noting that this study was relatively small. The researchers also point out that most of the SSc patients were already receiving standard treatments, including immunosuppression. This means that the findings might be influenced by the treatments the patients were on, and the differences observed might need to be confirmed in larger groups of patients.
In Conclusion: This research provides valuable new insights into the complex world of fibroblasts in systemic sclerosis. By carefully separating and characterising different fibroblast populations, the study highlights the crucial role of a specific non-migratory type, particularly in the later stages of the disease. Pinpointing these key cellular players and the signals that influence them brings us closer to developing more precise and effective treatments for SSc.
Characterisation of a pathogenic non-migratory fibroblast population in systemic sclerosis skin. JCI Insight. (2025). https://doi.org/10.1172/jci.insight.185618
Journal information: https://insight.jci.org
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