Understanding Systemic Sclerosis: New Insights into a Complex Disease

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Systemic sclerosis (SSc), also known as scleroderma, is a rare autoimmune disease that causes the hardening and scarring of the skin and internal organs. It’s a serious condition with limited treatment options, and it has the highest mortality rate among all rheumatic diseases. But new research is shedding light on the complex processes behind SSc, offering hope for better treatments in the future.

Mapping the disease: Scientists have used advanced techniques to create detailed maps of the skin of both healthy people and those with SSc. These aren't just ordinary maps; they show the location of different cells and their activity at a molecular level.

  • Spatial Transcriptomics: Researchers used methods called spatial transcriptomics (ST) to profile the skin. This allows them to see which genes are active in different parts of the tissue. Think of it like having a super-detailed map showing which houses are lit up at night and how bright each light is.
  • Single-cell RNA sequencing: They also used single-cell RNA sequencing (scRNA-seq) which lets them study individual cells and identify different cell types and their unique functions. This allowed them to create a comprehensive atlas of human skin, identifying a number of cell types including fibroblasts, macrophages, keratinocytes, and endothelial cells.
By combining these two technologies, the scientists could see how the cells in the skin are organized and how they interact with each other. They found that in SSc, there's a specific "fibrotic niche" or area that's enriched with certain cells, particularly fibroblasts and macrophages. This niche is significantly larger in SSc patients, and it seems to be linked to how severe their disease is.

Fibroblasts - The key players: Fibroblasts are cells that produce the material that makes up connective tissue in the body, called the extracellular matrix (ECM). In SSc, these cells go into overdrive and produce too much ECM, leading to fibrosis or scarring. The researchers found that there are different types of fibroblasts:
  • SCARA5+ Fibroblasts: These are like the starter cells, also known as progenitor fibroblasts. They seem to be important for maintaining normal tissue. In SSc, their numbers are reduced.
  • POSTN+ and ACTA2+ Fibroblasts: These are the more mature, or terminally differentiated, myofibroblasts, responsible for producing a lot of ECM and contributing to fibrosis. They are increased in SSc.

The scientists also found that the SCARA5+ fibroblasts can turn into the POSTN+/ACTA2+ fibroblasts. This process is like a recipe where the ingredients are changing, and it highlights how cells in SSc transition from a healthy state to a disease state.

Macrophages - The immune messengers: Macrophages are immune cells that usually help to clean up debris and fight infection. However, in SSc, they seem to play a role in promoting fibrosis. The study identified different types of macrophages:
  • Proinflammatory macrophages: These macrophages release substances that cause inflammation. They were found to be significantly increased in SSc.
  • Phagocytic macrophages: These macrophages are responsible for engulfing and removing debris. Their numbers are reduced in SSc.
  • Antigen-presenting macrophages: These macrophages help the immune system to recognize and respond to threats.

The researchers observed that the proinflammatory macrophages and fibroblasts are located near each other within the fibrotic niche. This close proximity suggests they are communicating with each other and contributing to disease progression.

Cellular Communication: The scientists investigated how fibroblasts and macrophages communicate using chemical signals. They found that:
  • CXCL12/CXCR4 Interaction: A chemical signal called CXCL12 can bind to a receptor called CXCR4 on macrophages, which helps to recruit these proinflammatory immune cells to the fibrotic niche.
  • ACKR3 in Fibroblasts: Interestingly, fibroblasts, particularly the starter cell type (SCARA5+), also have a receptor called ACKR3. This receptor can bind to the same chemical signal, CXCL12, and it acts as a "scavenger" which could help to regulate the levels of the signal in healthy tissue. In SSc, the researchers observed that the levels of ACKR3 were reduced, which might allow the levels of the chemical signal, CXCL12 to increase and thus draw more immune cells, which contribute to the development of fibrosis.

Implications for treatment: This research gives us a new way of thinking about SSc. It shows that the disease is not just about individual cells, but also about how these cells are organized and how they communicate with each other. By identifying key players, like the different types of fibroblasts and macrophages, as well as their signaling pathways, we might be able to find new ways to treat this complex disease. Some potential strategies could include: Targeting the communication between fibroblasts and macrophages, Modulating the different types of fibroblasts to shift them from a fibrotic to a more healthy state and Regulating the CXCL12/CXCR4 interaction to reduce inflammatory cell recruitment.

The study also suggests that the imbalance of different types of macrophages is important. By targeting specific types of macrophages, we might be able to reduce the inflammation that drives the disease.

Conclusion: This research is a big step forward in our understanding of SSc. By using advanced technologies to map the disease at a cellular level, scientists are uncovering new targets for treatment. While there's still much work to be done, this study provides a strong foundation for developing more effective therapies for people living with SSc. The team’s detailed analysis of cell-cell communications provides an exciting avenue for identifying specific molecules that could be targeted to disrupt disease progression and restore balance within the skin.
 
Additional information: Mapping spatially-resolved transcriptomes in systemic sclerosis. BioRxiv (2025). https://doi.org/10.1101/2025.01.14.632962

Journal information: https://www.biorxiv.org/

Location: Oxford, UK

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