Unlocking the Secrets of Fibrosis: New Insights into Scleroderma
Image credit: https://openai.com/index/dall-e/
Systemic sclerosis (SSc), also
known as scleroderma, is a complex condition where the body's immune system
goes awry. It leads to inflammation and, crucially, extensive fibrosis,
where tissue thickens and scars. This primarily affects the skin, but can also
impact internal organs, leading to organ failure and serious health problems. A
key part of this process is played by cells called fibroblasts, which
are responsible for producing the stuff that makes up the tissue, called the
extracellular matrix.
For a long time, scientists have known that fibroblasts aren't all the same; they're a diverse bunch with different functions. However, it’s only recently that new technology has allowed researchers to really delve into understanding these differences, and how they play a role in diseases such as SSc.
A new way to look at cells
Traditionally, scientists have used techniques like single-cell RNA sequencing(scRNA-seq) to study cells. This method allows them to see which genes are
active in each cell, giving clues about their functions. However, there’s a
problem; to do this, the tissue has to be broken up into individual cells,
meaning you lose important information about where the cells are located
within the tissue and how they interact with each other.
To overcome this, researchers
have started using a new approach called cyclic in-situ hybridization (cISH).
This is a technique that lets them measure gene activity in individual cells,
but importantly, while still within the intact tissue. Think of it like
a very detailed, high-resolution map of the cells and their activities in their
natural environment.
What did they find?
By using cISH, scientists were able to identify not just the usual types of cells such as keratinocytes, immune cells and endothelial cells, but also different kinds of fibroblasts. Using this new method, they discovered nine different types of fibroblasts and, crucially, their specific locations and roles.
By using cISH, scientists were able to identify not just the usual types of cells such as keratinocytes, immune cells and endothelial cells, but also different kinds of fibroblasts. Using this new method, they discovered nine different types of fibroblasts and, crucially, their specific locations and roles.
Here are some of the key
fibroblast types identified:
What does it mean for SSc?
The study showed that in SSc, some of these fibroblast types become more
frequent, particularly the SFRP2+ RetD and COL8A1+ types. Not only were
there changes in the quantity of each type, but also changes in their
activation status, pushing the tissue towards more fibrosis. Additionally, the
study revealed that specific locations in the skin, called cellular neighborhoods
(CNs), where different cells interact, were also altered in SSc. For example,
some CNs showed increased immune cell activity, especially with
inflammatory and fibrosis-promoting cells, and some of these were uniquely
present in SSc skin.
- SFRP2+ RetD FB: Found deeper in the skin (reticular dermis), these fibroblasts showed the highest production of extracellular matrix. This means they are likely a key driver of the fibrosis seen in SSc.
- SFRP2+ PapD FB: Located closer to the skin's surface (papillary dermis), these fibroblasts were found to have different functions from the SFRP2+ RetD FB, being involved in things like hemostasis or stopping blood loss.
- CCL19+ nonPV FB: These cells were found throughout the dermis, and seem to be a more inflammatory type of fibroblast.
- CCL19+ PV FB: Found around blood vessels, this subpopulation was different from the nonPV group with a higher expression of endothelial cell markers.
- COL8A1+ FB: These fibroblasts play a role in both the production of collagen and immune cell recruitment.
- PI16+ FB: This type is thought to have some stem cell-like properties and could differentiate into other types of fibroblasts.
The researchers also found that some fibroblasts, such as the COL8A1+ FB, started to interact with immune cells in SSc, which they didn't do in healthy skin. This shows that cell-to-cell communication plays a vital role in the development of SSc. They could also demonstrate that specific fibroblast populations that are spatially close to monocytes/macrophages were more frequent in patients whose fibrosis worsened over time. This suggests the possibility of a new predictive biomarker.
The bigger picture: This research highlights the importance of considering not just what cells are present, but also where they are and who they are talking to. This new knowledge about the types of fibroblasts and how they act in the skin of SSc patients, provides a platform for future research. Scientists can now use this data to look for ways to target these specific cells and communication pathways with new treatments. The hope is that this could lead to more effective therapies that prevent the progression of fibrosis and improve the lives of people living with SSc.
Additional information: https://www.biorxiv.org/
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