Single-Cell Analysis of Debrided Diabetic Foot Ulcers Reveals Dysregulated Wound Healing Environment in Non-Hispanic Black Patients

Abstract

Diabetic foot ulcer is a critical complication of diabetes, but the wound microenvironment and its healing process are not completely understood. In this study, we optimized single-cell profiling from sharp debrided ulcers. Our findings demonstrate that healing diabetic foot ulcers were significantly enriched with distinct fibroblasts-expressing genes related to inflammation (CHI3L1, IL6) and extracellular matrix remodeling (ASPN), validating our previous studies on surgically resected ulcers. The race-focused analysis depicted lower expression of key healing-associated genes such as CHIL3L1, matrix metalloproteinase 11 gene MMP11, and SFRP4 in fibroblasts of non-Hispanic Black patients than in those of White patients. In cellular communication analysis, healing-enriched fibroblasts of non-Hispanic Black patients exhibited upregulation of signaling pathways such as WNT, whereas those of White patients showed insulin-like GF and Midkine pathways upregulation. Our findings advocate race as a risk marker of diabetic foot ulcer outcomes, likely reflecting underlying disparities in environmental exposures and access to care that profoundly influence healing markers. Using sharp debrided tissues for single-cell assays, this study highlights the need for in-depth investigations into dysregulated wound healing microenvironments of under-represented racial groups.