Shared and specific fibroblast cell types across tissues

                                                                     Image credit: https://openai.com/index/dall-e/   

Imagine your body is like a bustling town, and within this town, you've got all sorts of workers doing different jobs. Fibroblasts are one of these key groups of workers. They're cells that are found all over the body, and they're usually known for producing the stuff that holds our tissues together, like scaffolding – what scientists call the extracellular matrix. They're also involved in keeping things ticking over normally.

However, in conditions like cancer, it turns out these fibroblasts can become a bit more complicated. Scientists have started to realise that not all fibroblasts are the same; there's a lot of variety amongst them, which they call heterogeneity. Understanding this variety – these different types, or subtypes, of fibroblasts – is really important for figuring out how they behave and how they interact with other cells, especially in a disease like cancer.

Now, a team of researchers has taken a deep dive into this world of fibroblasts. They've gathered a massive amount of data from 73 different studies, looking at nearly a quarter of a million (249,156) fibroblasts from 10 different types of tissue in the human body. This is a really comprehensive look, aiming to create a sort of "fibroblast atlas" to help us understand their complexity.

What they've found is quite revealing. By analysing the genes that these fibroblasts express (their transcriptome), the researchers were able to identify 18 distinct subtypes of fibroblasts. Think of it like discovering 18 different job roles within the fibroblast workforce, each with its own set of tools and responsibilities.

One of the most interesting discoveries was a previously undescribed type of fibroblast which they've named TSPAN8+ chromatin remodelling fibroblasts. This is a new player on the scene, and it seems to have some unique characteristics. For instance, these cells show high levels of activity in genes related to modifying the structure of DNA(histone modification) and reorganising the material inside the cell's nucleus (chromatin remodelling). The researchers were even able to spot these TSPAN8+ fibroblasts in real tissue samples using special techniques that map out where different molecules are located (spatial transcriptomics and multiplexed immunofluorescence).

Compared to other fibroblast subtypes, these TSPAN8+ chromatin remodelling fibroblasts seem to be more involved in cell differentiation (the process of a cell becoming more specialised) and appear to be like resident fibroblasts, meaning they tend to stay put in the tissues. Intriguingly, they seem to chat a lot with blood vessel cells (endothelial cells) and a type of immune cell called T cells. They do this through specific signals: they produce a molecule called VEGFA, which talks to a receptor called F2R on other cells. Perhaps most concerningly, the presence of these TSPAN8+ chromatin remodelling fibroblasts was linked to a poorer prognosis in cancer patients.

The study also looked at how these different fibroblast subtypes are distributed across various tissues and in different types of samples, like normal tissue, tissue next to a tumour, the tumour itself, and even metastatic sites (where cancer has spread). They found that some subtypes, like MMP11+ myofibroblasts and CFD+ inflammatory fibroblasts, were quite common across many tissues. However, the proportion of each subtype could vary quite a bit depending on the tissue. Notably, several subtypes, including the TSPAN8+ chromatin remodelling fibroblasts, were found in higher numbers in tumour samples.

The researchers also investigated the potential origins of these fibroblast subtypes, suggesting that some might arise from resident tissue fibroblasts, while others, like certain antigen-presenting fibroblasts, might even come from other types of cells. They also explored how fibroblast subtypes relate to ageing and cellular senescence (a state where cells stop dividing). Different subtypes showed different patterns with age, and some were more prone to senescence than others.

Crucially, the study delved into how these fibroblast subtypes interact with other cells in their environment. They found that fibroblasts communicate a lot with each other, as well as with endothelial cells and epithelial cells (cells that line surfaces in the body), more so than with immune cells. However, certain subtypes had specific interactions. For example, CFD+ inflammatory fibroblasts seem to play a role in immune modulation, talking to T cells, B cells, and macrophages. The TSPAN8+ chromatin remodelling fibroblasts, as mentioned earlier, had notable interactions with endothelial cells and T cells.

Finally, the researchers explored the clinical significance of these fibroblast subtypes, particularly the newly identified TSPAN8+ chromatin remodelling ones. They found that higher levels of these fibroblasts were associated with worse survival in several types of cancer. They also looked at whether these fibroblasts could predict how patients would respond to immunotherapy, a type of cancer treatment that harnesses the body's immune system. Initial findings suggest that in some cancers, higher levels of TSPAN8+ chromatin remodelling fibroblasts might be linked to a poorer response to immunotherapy. However, in other contexts, like in certain colorectal cancers, they seemed to be more enriched in patients who had a good response. This suggests the role of these fibroblasts in treatment response might be complex and depend on the specific type of cancer.

In essence, this study provides a much more detailed map of the fibroblast landscape in the human body, particularly in the context of cancer. By identifying these 18 subtypes and highlighting the unique characteristics of the TSPAN8+ chromatin remodelling fibroblasts, this research opens up new avenues for understanding how cancer develops and progresses, and potentially for developing more targeted therapies that focus on these specific fibroblast populations. To help other researchers in this field, the team has even created an online tool, the Fibroblast Atlas. This comprehensive work underscores the fact that the fibroblast workforce in our body is far more diverse and specialised than we previously thought, and understanding these nuances could be key to tackling complex diseases like cancer.

 

Additional information: Fibroblast atlas: Shared and specific cell types across tissues. Science Advances (2025). https://www.science.org/doi/10.1126/sciadv.ado0173

Journal information: https://www.science.org/journal/sciadv