Scientists Map Fibroblasts, Uncover New Drug Targets in Diseases

Researchers have made significant strides in understanding fibroblasts, a type of cell that plays a crucial role in various diseases affecting multiple organs. For the first time, scientists at the Wellcome Sanger Institute, in collaboration with the Universities of Cambridge and Newcastle, have mapped these underappreciated scaffolding cells in skin. Their findings, published on September 24, 2023, in the journal Nature Immunology, reveal how fibroblasts can become dysfunctional across a range of conditions, from acne and psoriasis to rheumatoid arthritis and inflammatory bowel disease.

The research team utilized advanced techniques, combining single-cell sequencing and spatial genomics with machine learning. This innovative approach allowed them to identify eight different fibroblast types and how these cells form distinct “tissue neighborhoods” in the skin. These neighborhoods indicate shared functions in various diseases, pointing to the potential of fibroblasts as universal drug targets.

Understanding the roles of fibroblasts is vital, given that skin is the largest organ in the body and serves as a primary barrier against infections. In the UK alone, two in three individuals will experience a skin disease during their lifetime. Skin disorders contribute to 24 percent of the country’s overall illness burden, with wound care alone costing the National Health Service approximately £8.3 billion annually.

Fibroblasts, found in every organ, are essential for wound healing and tissue repair. Despite their importance, these cells have not received adequate attention in medical research, partly due to their diversity and complexity. The researchers’ study aimed to illuminate this complexity by mapping fibroblasts in human skin samples, including those from individuals with 23 different skin disorders.

The team generated spatial transcriptomic data, which measures gene expression across various locations within a tissue. This data revealed that fibroblasts in healthy skin form distinct neighborhoods with specific functions. Following this, the researchers expanded their analysis to other organs, including the endometrium, gut, and lung, across 14 diseases such as inflammatory bowel disease and lung cancer.

Their findings highlighted three “rogue” fibroblast subtypes that appear across organs and multiple diseases, including scarring diseases and rheumatoid arthritis. Notably, the same activated fibroblasts that recruit immune cells to early skin wounds were found in inflammatory conditions like acne and inflammatory bowel disease. This suggests that fibroblasts may adopt a wound-like state to draw immune cells into tissues affected by these diseases.

By identifying shared and disease-specific fibroblasts within these distinct tissue neighborhoods, the researchers have opened the door to the development of universal drug targets. Such advancements could lead to the creation of therapies that address multiple diseases simultaneously.

The team aims to extend their research to include various cell types across all human tissues. They plan to leverage machine learning and artificial intelligence to identify disease-specific neighborhoods that can be targeted for therapeutic interventions.

Dr. Lloyd Steele, first author of the study, emphasized the importance of this research in understanding fibroblasts. He stated, “We’ve shown for the first time that fibroblasts occupy and maintain distinct anatomical microenvironments in skin tissue in health and disease.”

Dr. Mo Lotfollahi, senior author and Group Leader at the Wellcome Sanger Institute, noted the transformative potential of artificial intelligence in scientific research. He remarked, “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.”

Matthew Patey, OBE, Chief Executive Officer of the British Skin Foundation, highlighted the significance of this innovative research. He stated, “Identifying a universal drug target in scaffolding cells found across the body opens the door to treatments that could benefit millions.”

Professor Muzz Haniffa, lead author and Head of Cellular Genomics at the Wellcome Sanger Institute, further stressed the clinical relevance of this work. He mentioned that it could save time and money in drug development while reducing potential side effects for patients.

The research represents a pivotal shift in how scientists understand and approach the role of fibroblasts in health and disease, paving the way for future innovations in treatment strategies.