Diabetic foot ulcers debridement SCRNA-seq showed healing association with inflammatory fibroblasts in minorities

In this pilot study, we optimized diabetic foot ulcers (DFUs) single-cell profiling from debrided DFUs of underrepresented African American (AA) patients. The healing-DFUs were significantly enriched (P=0.03) with unique heterogenous Healing-associated Fibroblasts (HE-Fibro), expressing inflammation (CHI3L1), ECM-remodeling (MMP13, ASPN) and wound healing (NRG1, COL7A1) associated genes, validating our previous findings with surgically resected healer-DFUs. HE-Fibro/Fibro cells depicted significantly lower expression of key healing-associated CHIL3L1, and TIMP1 genes in AAs compared to Whites, signifying race-associated heterogeneity. Reparative M2 macrophages were enriched in Healing-DFUs (P=0.05), while inflammatory M1 macrophages displayed distinct transcriptome differences in Nonhealing-DFUs and Healing-DFUs. Cellular communication analysis revealed a pivotal role for HE-Fibro/Fibroblasts (signal-senders) and M1 (signal-receivers). HE-Fibro’s signaling significantly upregulated wound-resolving WNT, and ECM-remodeling CXCL pathways in Healing-DFUs, while M1 signaling upregulated healing-disruptive, and inflammation-associated, SPP1 pathways, in Nonhealing-DFUs. This study justifies using debrided tissues for single-cell assays and highlights the need for in-depth investigations into dysregulated wound healing microenvironments in AAs.