Decoding the Human Skin Ulcer Niche using Spatial Transcriptomics and Bioinformatics

Abstract

What is already known about this subject?

Venous leg ulcers (VLUs) are the most common form of chronic wounds and often arise from lipodermatosclerosis (LDS), a fibrotic pre-ulcer condition caused by chronic venous insufficiency. Despite their prevalence and burden, the molecular mechanisms driving the transition from LDS to VLU remain poorly defined. Most previous studies have relied on bulk transcriptomics or single-cell approaches, which lose critical spatial context and therefore cannot fully capture the architecture and heterogeneity of chronic wounds.

What are the new findings?

This study provides the first spatial transcriptomic comparison of LDS and VLU tissue using the high-resolution Visium HD platform. LDS tissue was characterized by uniform extracellular matrix producing fibroblasts and terminally differentiating keratinocytes, reflecting a fibrotic dermal state. In contrast, VLUs exhibited marked heterogeneity, with epidermal clusters showing both hyperproliferative and terminal keratinocyte states, dermal infiltrates dominated by plasma cells, and fibroblast subtypes spanning fibrotic, vascular, inflammatory, and endothelial-like programs. These findings reveal distinct cellular niches that underpin fibrotic stability in LDS versus disrupted repair in VLUs.

How might it impact on the field in the foreseeable future?

By providing a spatially resolved map of chronic venous disease progression, this study identifies fibroblast and immune subtypes as potential therapeutic targets and highlights biological programs that may drive wound progression. These insights lay the foundation for translational strategies to stratify patients according to fibrotic (LDS) or inflammatory/heterogeneous (VLU) phenotypes, with potential to inform more precise and effective management of chronic wounds.