Deciphering the Dysregulating IGF-1-SP1-CD248 Pathway in Fibroblast Functionality during Diabetic Wound Healing

Reduced fibroblast activity is a critical factor in the progression of diabetic ulcers. CD248, a transmembrane glycoprotein prominently expressed in activated fibroblasts, plays a pivotal role in wound healing. However, the role of CD248 in diabetic wound healing and the CD248 regulatory pathway remains largely unexplored. Our study shows that CD248 expression is significantly reduced in skin wounds from both patients and mice with diabetes. Single-cell transcriptome data analyses reveal a marked reduction of CD248-enriched secretory-reticular fibroblasts in diabetic wounds. We identify IGF-1 as a key regulator of CD248 expression through the protein kinase B/mTOR signaling pathway and the SP1 transcription factor. Overexpression of CD248 enhances fibroblast motility, elucidating the under-representation of CD248-enriched fibroblasts in diabetic wounds. Immunohistochemical staining of diabetic wound samples further confirms low SP1 expression and fewer CD248-positive secretory-reticular fibroblasts. Further investigation reveals that elevated TNFα levels in diabetic environment promotes IGF-1 resistance, and inhibiting IGF-1 induced CD248 expression. In summary, our findings underscore the critical role of the IGF1-SP1-CD248 axis in activating reticular fibroblasts during wound-healing processes. Targeting this axis in fibroblasts could help develop a therapeutic regimen for diabetic ulcers.