Study Identifies PIEZO2-Expressing Cells Driving Keloid Recurrence

Keloids are raised, overgrown scars that often cause chronic pain, itching, and movement restriction. Management is challenging, with recurrences after treatment reaching thirty percent. Unlike hypertrophic scars, the unchecked growth in keloids likely stems from an overproduction of extracellular matrix collagen by fibroblasts. Repeated mechanical tension is believed to contribute, but the specific cellular mechanisms remained poorly understood.

A research team at Chiba University, led by Professor Yuzuru Ikehara, explored the origins of keloid formation by examining differences between keloids and other forms of tissue fibrosis, particularly lymphedema. The team conducted a detailed comparative analysis using tissue samples from keloids, lymphedema, and healthy skin. Employing global gene expression profiling and single-cell RNA sequencing, the team aimed to identify cell types and biological pathways unique to keloid pathology.

Results revealed that keloid tissue expresses much higher levels of PIEZO2, a mechanosensitive ion channel, than lymphedema. PIEZO2 acts as a cellular sensor, detecting and responding to physical stresses. In keloids that had recurred after surgery, PIEZO2 expression was even greater. Through single-cell analysis, researchers identified a novel subgroup of fibroblasts, termed FB^PZ2+, that produce high levels of PIEZO2. These cells are highly active in generating collagen and extracellular matrix, forming the backbone of scar tissue. FB^PZ2+ fibroblasts were found clustering around blood and lymphatic vessels, especially in areas of active keloid growth.

Professor Ikehara highlighted the importance of examining all connective tissue cell types to fully grasp keloid homeostasis and formation. “Connective tissue is not composed merely of fibroblasts—it also contains immune cells, blood vessels, and nerves, all of which work together to maintain the proper homeostasis, a critical factor in supporting organ-specific functions,” explains Prof. Ikehara. “Therefore, just as studies of immune and neural cell components have advanced our understanding of neurodegenerative and allergic diseases, investigating fibroblasts may help uncover the mechanisms underlying keloid formation.”

Most significantly, the findings offer new directions for diagnosing and managing keloids. “Our work offers new insights into the pathogenesis of keloids and opens the door to novel diagnostic and therapeutic strategies,” adds Prof. Ikehara. “For example, PIEZO2 inhibitors, which are a type of calcium ion channel blocker, may help alleviate pain and itching associated with keloids. If such targeted therapies become clinically available, they could greatly improve the quality of life for patients suffering from keloid-related discomfort.”