Identification of a physiologic vasculogenic fibroblast state to achieve tissue repair

Tissue injury to skin diminishes miR-200b in dermal fibroblasts. Fibroblasts are widely reported to directly reprogram into endothelial-like cells and we hypothesized that miR-200b inhibition may cause such changes. We transfected human dermal fibroblasts with anti-miR-200b oligonucleotide, then using single cell RNA sequencing, identified emergence of a vasculogenic subset with a distinct fibroblast transcriptome and demonstrated blood vessel forming function in vivo. Anti-miR-200b delivery to murine injury sites likewise enhanced tissue perfusion, wound closure, and vasculogenic fibroblast contribution to perfused vessels in a FLI1 dependent manner. Vasculogenic fibroblast subset emergence was blunted in delayed healing wounds of diabetic animals but, topical tissue nanotransfection of a single anti-miR-200b oligonucleotide was sufficient to restore FLI1 expression, vasculogenic fibroblast emergence, tissue perfusion, and wound healing. Augmenting a physiologic tissue injury adaptive response mechanism that produces a vasculogenic fibroblast state change opens new avenues for therapeutic tissue vascularization of ischemic wounds. Here, the authors report on the discovery of physiological vasculogenic fibroblasts capable of forming functional blood vessels. In vivo tissue reprogramming triggered by topical tissue nanotransfection (TNT) of a single anti-miR-200b oligonucleotide achieved therapeutic tissue vascularization.

Automated summary

Skin injury reduces miR-200b levels in dermal fibroblasts, but inhibiting this miRNA can lead to the emergence of a vasculogenic fibroblast subset capable of forming functional blood vessels. This vasculogenic fibroblast state change can be achieved through topical tissue nanotransfection of a single anti-miR-200b oligonucleotide, providing a potential therapeutic approach for tissue vascularization in ischemic wounds.