Scaffolding cells could be key to targeting diseases, says study

Scientists from the Wellcome Sanger Institute, the universities of Cambridge and Newcastle, together with other colleagues, described their findings in Nature Immunology.

Fibroblasts play a key role in the formation of the extracellular matrix and are present in skin and the organs of the human body.

Dr Lloyd Steele, first author at the Wellcome Sanger Institute and Cambridge university, said: “Fibroblasts have critical roles in recruiting immune cells to skin tissue and causing scarring, which can result in a range of skin diseases

However, he added: “We lack highly effective treatments to treat scarring in clinical practice, partly because these cells have been poorly understood.”

The researchers identified eight different types that form what they label ‘tissue neighbourhoods’ and are involved in wound healing, scarring, tissue repair, the development of connective tissues and maintenance of skin.

Five different types of fibroblasts were identified in healthy skin alone, located in neighbourhoods linked to specific functions.

The scientists went on to study fibroblast and tissue neighbourhoods in major organs including the endometrium, gut and lung featured in cases of 14 different diseases.

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

Their work revealed that activated fibroblasts which recruit immune cells to early skin wounds were present too in inflammatory diseases.

The existence of disease-related and disease-specific fibroblasts in tissue neighbourhoods across multiple diseases and organs suggests the possibility of developing single drugs that work for several diseases, said the researchers.

While fibroblasts increase collagen production and develop muscle-like fibres to contract after wounding, it had been unclear previously how these adapt in the case of diseases, said Steele.

“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,” he commented. 

The team, whose study was part of the international Human Cell Atlas (HCA) consortium mapping all human cells, had generated spatial transcriptomic data to map the identified fibroblast populations from normal and diseased human skin. 

Lead author professor Muzz Haniffa, head of cellular genomics at the Wellcome Sanger Institute and Newcastle University professor of dermatology and immunology explained the wider implications of their research.

“The clinical relevance of our work is huge – it is paradigm-shifting,” declared Haniffa.

“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.”

The skin fibroblast dataset is freely available to view and download here. 

Pic: Shutterstock (Olga Zinkevych) A 3D model of fibroblasts, collagen and elastic fibres in the extracellular matrix structure.