Healing Diabetic Wounds with Vasculogenic Fibroblasts ft. Kanhaiya Singh, PhD

In this episode of MD Newsline, Dr. Kanhaiya Singh, associate professor at the University of Pittsburgh, discusses his research into vasculogenic fibroblasts and their potential role in healing diabetic and ischemic wounds. He explains how a subset of fibroblasts can acquire vasculogenic properties while retaining their fibroblast identity, a process he describes as a state change rather than a fate change. Dr. Singh explores how diabetes and epigenetic changes can suppress the generation of vasculogenic fibroblasts, the role of miR-200b in regulating this process, and findings from lineage-tracing studies in animal models. He also discusses tissue nanotransfection as a potential approach for delivering anti-miR-200b to wound tissue and the remaining steps needed to move this research toward clinical applications. Episode Highlights: The Discovery of Vasculogenic Fibroblasts Dr. Singh explains how single-cell RNA sequencing and subsequent experiments revealed a fibroblast population with vasculogenic properties. Unlike a conventional cell-fate change, these cells retain fibroblast characteristics while acquiring endothelial-like functions, leading the researchers to describe them as vasculogenic fibroblasts. State Change Rather Than Cell Fate Change The discussion explores the distinction between a cell changing its fate and acquiring a new functional state. Dr. Singh explains that vasculogenic fibroblasts continue to maintain fibroblast properties while taking on vasculogenic functions, allowing specific fibroblast subsets to participate in vascular repair without completely becoming endothelial cells. How Diabetes Suppresses Vasculogenic Fibroblasts Dr. Singh discusses how the diabetic microenvironment can interfere with vasculogenic fibroblast generation. He describes the role of hyperglycemia, DNA methyltransferases, and DNA hypermethylation in suppressing the endothelial program needed for vasculogenic fibroblast production. The Role of miR-200b The conversation examines miR-200b, an epigenetic regulator that plays a central role in the emergence of vasculogenic fibroblasts. Dr. Singh explains how elevated miR-200b in diabetic fibroblasts may limit their vasculogenic capacity and how reducing miR-200b can promote the phenotype needed for vascular repair. Lineage Tracing and Vasculogenic Fibroblast Evidence Dr. Singh describes experiments using Col1a2-Cre mouse models and lineage tracing to investigate whether fibroblasts contribute directly to vascular structures. He discusses findings showing fibroblast lineage-labeled cells within CD31-positive blood vessels and explains how spatial transcriptomics is helping identify the fibroblast subsets involved in this process. Vasculogenic Fibroblasts in Chronic Wounds The discussion highlights how vasculogenic fibroblasts are diminished in chronic, diabetic, and ischemic wounds. Dr. Singh shares findings from mouse models suggesting that increasing the proportion of vasculogenic fibroblasts can improve wound closure and perfusion. Tissue Nanotransfection and miR-200b Targeting Dr. Singh explains how tissue nanotransfection uses a silicon chip with microneedles and a pulsatile electrical current to deliver genetic cargo into tissue. In this research, the approach is being used to deliver an antisense oligonucleotide targeting miR-200b with the goal of restoring vasculogenic activity within wound tissue. From Preclinical Research Toward Clinical Translation The interview explores what remains between the current research and potential clinical studies. Dr. Singh discusses ongoing work with human skin explants, the development of a proprietary wound-healing model, and efforts to make the tissue nanotransfection device FDA-compatible before advancing toward clinical applications. The Future of Epigenetic Biomarkers in Diabetic Wound Care Looking ahead, Dr. Singh highlights epigenetics as an important area of research, particularly the development of biomarkers that could help predict whether diabetic wounds will heal or recur. He also discusses the potential role of artificial intelligence in analyzing single-cell data and developing predictive biomarkers through the Diabetic Foot Consortium. Key Takeaway Vasculogenic fibroblasts represent a distinct fibroblast state that may contribute to vascular repair during wound healing. Dr. Singh's research suggests that diabetes can suppress this reparative capacity through epigenetic mechanisms involving miR-200b, while approaches such as tissue nanotransfection may offer a potential way to restore vasculogenic activity. Although this work remains in the preclinical and translational research stage, continued investigation into epigenetic biomarkers and tissue reprogramming could help advance new approaches to diabetic wound healing. Resources: Website: https://mdnewsline.com/ Newsletter: https://mdnewsline.com/subscribe/