Pushing the boundaries of science: Following the Fibroblasts

Over the past several decades, scientists have built a detailed catalogue of the many and varied immune cells in our body, and the parts they play in maintaining health and driving disease. Based on this knowledge, new therapies for diseases where the immune system is involved, ranging from autoimmune disease to fibrosis and cancer, target the immune system. Yet while these medicines work well for some patients, for others they don’t make a positive difference, or their bodies develop resistance to the therapies over time.

One potential reason for this critical medical gap is the relatively poor scientific understanding of cells, known as fibroblasts, that make up the support and connective structures of tissues, and how they behave in disease. Unlike immune cells, a full catalogue of the many flavours of fibroblasts, including tissue-specific and shared subtypes, has been missing.

Without that knowledge, it is unclear whether there are similarities among fibroblasts in different tissues and disease contexts, or whether fibroblasts are bystanders or active players in diseases. And that, in turn, makes it impossible to develop new therapies targeting rogue fibroblasts. As Andreas Frei, Head of Biomarkers and Translational Technologies for Immunology at Roche, noted, “We need to understand the cell types before we can understand the interactions between them.”

Five years ago, with this goal in mind, interested scientists in Roche Pharma Research and Early Development convened a consortium of top researchers in the field across academic centres and within Roche. Now, their research is coming to fruition: they have identified similar fibroblasts across several diseases in different organs, and are beginning to describe the fibroblast landscape of individual disorders as well.

In ain the scientific journal Med, the research network studied the fibroblasts from patients with four diseases: Sjögren’s syndrome, interstitial lung disease, inflammatory bowel disease and rheumatoid arthritis. They used new techniques that allowed them to determine the gene expression patterns of individual fibroblast cells, which they could then use to classify the cells into different types and across the different tissues studied.

This approach allowed them to find two particularly interesting fibroblast types that appeared to actively contribute to chronic inflammation across all four diseases and tissues they studied. One type seems to communicate primarily with immune cells, while the other talks to blood vessels.

Another study, appearing inis the first to come in a series from the network characterising the fibroblast landscape of particular diseases, in this case inflammatory bowel disease. By describing both common and unique features of fibroblasts in different diseases, the researchers hope to guide the development of the most effective drugs targeting fibroblasts in different conditions.

Arriving at these detailed fibroblast descriptions was not simple. The Roche Fibroblast Network Consortium had to figure out different solutions for isolating the fibroblasts from different tissues, all while the technology they needed to study them was rapidly evolving.

However, the enthusiasm and expertise of the group enabled them to take on these challenges and provide important biological insights.

More broadly, the research has started to build a common language that can serve as the basis for future exploration and hopefully one day complement existing therapy options for a wide range of diseases. “15 years ago, people weren’t talking about these cells in inflammatory diseases at all. It’s been a paradigm shift in the last decade,” said Kara Lassen, Head of Immunology Discovery at Roche.