Keloidal Collagen May Be Produced Directly by alpha SMA-positive Cells: Morphological Analysis and Protein Shotgun Analysis

Background:Keloids are fibroproliferative lesions caused by abnormal dermal wound healing. Keloidal collagen (KC) is a pathognomic feature of keloids, but the mechanism by which it forms is unknown. This study aimed to evaluate the histopathology of KC and thereby gain clues into how it forms. Methods:The cross-sectional study cohort consisted of a convenience series of patients with keloids who underwent surgical excision. Skin pieces (3 mm(2)) were collected from the keloid center and nearby control skin. Histopathology was conducted with light and electron microscopy and immunohistochemistry. KC composition was analyzed with protein shotgun analysis. Results:Microscopic analyses revealed the ubiquitous close association between KC and alpha SMA-positive spindle-shaped cells that closely resembled myofibroblasts. Neither KC nor the spindle-shaped cells were observed in the control tissues. Compared with control skin, the collagen fibers in the KC were overall thinner, their diameter varied more, and their spacing was irregular. These features were particularly pronounced in the collagens in the vicinity of the spindle-shaped cells. Protein shotgun analysis did not reveal a specific collagen in KC but showed abnormally high abundance of collagens I, III, VI, XII, and XIV. Conclusions:These findings suggest that KC may be produced directly by myofibroblasts rather than simply being denatured collagen fibers. Because collagens VI and XII associate with myofibroblast differentiation, and collagen XIV associates with local mechanical stress, these collagens may reflect, and perhaps contribute to, the keloid-specific local conditions that lead to the formation of KC.