Scientists show for the first time how fibroblasts go 'rogue' in different diseases

Scientists have mapped underappreciated scaffolding cells in skin, known as fibroblasts. They show for the first time how fibroblasts go 'rogue' in many different diseases affecting multiple organs – from acne and psoriasis, to rheumatoid arthritis and inflammatory bowel disease.

Researchers at the Wellcome Sanger Institute, the Universities of Cambridge and Newcastle, and their collaborators combined single-cell sequencing and spatial genomics datasets with machine learning to identify eight different types of fibroblasts. They show how the fibroblasts form distinct 'tissue neighborhoods' in skin and reveal their shared functions in a range of diseases across various tissues.

Published today (24 September) in Nature Immunology, the researchers suggest that fibroblasts show potential as universal drug targets due to their involvement in multiple diseases across a range of tissues.

This study is part of the international Human Cell Atlas (HCA) consortium, which is mapping all human cells to understand human health, and help diagnose, monitor, and treat disease.

Skin is the largest organ in the body and plays an essential role in protecting us from infections. Two in three British people will suffer from skin disease at some point in their lifetime. Skin diseases account for 24 per cent of the UK's burden of illness, with wound care costing the NHS approximately £8.3 billion annually, and other skin conditions and diseases costing approximately £723 million each year.

Scaffolding cells, known as fibroblasts, are found in skin and every other organ in the body. They are involved in wound healing, scarring, tissue repair, the development of connective tissues and maintenance of skin.

Until now, skin fibroblasts have been somewhat overlooked, partly because their diversity has been difficult to study. While it is known that fibroblasts increase their collagen production and develop muscle-like fibres to contract after wounding, it has been unclear how fibroblast states change across the many diseases observed in skin, from cancers to acne.

Understanding the true diversity of fibroblasts and where they are located in tissues, in both health and disease, presents enormous clinical opportunities due to their roles in scarring and inflammation.

In a new study, Sanger Institute researchers and their collaborators set out to map fibroblasts in human skin, from healthy skin samples and 23 skin disorders, including psoriasis, lupus, skin cancers and acne.

The team generated spatial transcriptomic data – which measures gene expression and how it varies across different locations within a tissue – to spatially map the identified fibroblast populations from normal and diseased human skin.

The researchers found that these scaffolding cells are far more complex than was previously thought. The team discovered five different types of fibroblasts in healthy skin, which are located in distinct 'tissue neighbourhoods' associated with specific functions. Following this, the team looked at fibroblasts and their 'tissue neighbourhoods' in many other organs, including the endometrium, gut and lung in 14 diseases, such as inflammatory bowel disease and lung cancer. The team identified fibroblast populations shared across organs.

Using machine learning models, they identified three 'rogue' subtypes of fibroblasts that are present in different organs across multiple diseases, including scarring diseases and lung cancer, rheumatoid arthritis in joints and inflammatory bowel disease in the gut.

Interestingly, the researchers found that the same activated fibroblasts that recruit immune cells to early skin wounds were observed in inflammatory diseases, such as acne and inflammatory bowel disease. This suggests that a wound-like fibroblast state is used to attract immune cells to tissues in diseases like acne and inflammatory bowel disease, which both have a risk of scarring.

By identifying shared disease-related and disease-specific fibroblasts within these 'tissue neighbourhoods' across multiple diseases and organs, the researchers identify potential universal drug targets. This means researchers may be able to develop single drugs that work for several diseases across the body.

In the future, the team aims to extend this research to many other cell types across all of the tissues in the human body, and use machine learning and artificial intelligence to find disease-specific 'tissue neighbourhoods' that can be modulated for therapy.

Fibroblasts have critical roles in recruiting immune cells to skin tissue and causing scarring, which can result in a range of skin diseases. We lack highly effective treatments to treat scarring in clinical practice, partly because these cells have been poorly understood. Modern technologies now allow us to begin to understand these critical cells in unprecedented detail. We've shown for the first time that fibroblasts occupy and maintain distinct anatomical microenvironments in skin tissue in health and disease. Our data are freely available and we provide an online tool that can be used by researchers to map fibroblasts from their own studies, to expand our knowledge on fibroblasts in disease."

Dr. Lloyd Steele, first author at the Wellcome Sanger Institute and University of Cambridge

Dr Mo Lotfollahi, senior author and Group Leader at the Wellcome Sanger Institute, said: "Artificial Intelligence is going to be transformative in how we do science in the next 10 years, and guide how we explore vast datasets and make sense of complexities of the human body. Here we used machine learning to classify and map fibroblasts in healthy skin and many different diseases. In the future, we could use AI to query all of the different diseases affecting all of the different cell types in the various tissues across the body, to build a complete picture of what happens in health and disease."

This discovery highlights the kind of innovative research that can change the way we treat skin disease and beyond. Identifying a universal drug target in scaffolding cells found across the body opens the door to treatments that could benefit millions, and we're proud to support the researchers making this possible."

Matthew Patey, OBE, Chief Executive Officer at British Skin Foundation

Professor Muzz Haniffa, lead author and Head of Cellular Genomics at the Wellcome Sanger Institute, and Professor of Dermatology and Immunology at Newcastle University, said: "The clinical relevance of our work is huge – it is paradigm-shifting in terms of how we move from understanding the role of individual cell types to uncovering how disease-specific cell types form 'tissue neighbourhoods' that mediate inflammation. We find the same disease-related fibroblasts involved in several diseases across the body – atopic eczema, inflammatory bowel disease, rheumatoid arthritis – meaning we could find universal therapeutic targets in these cells to treat many diseases. This could save time and money in drug development, and reduce side effects for patients."