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Early Radial Extracorporeal Shockwave Stimulation on Proximal Tibial Circular Osteotomy Site Enhanced Heterotopic Skin Wound Healing via Small Extracellular Vesicles

ABSTRACT: Wound healing represents a complex biological process necessitating innovative therapeutic approaches, particularly for chronic wounds such as diabetic foot ulcers (DFUs). Inspired by the regenerative effects of tibial bone transport for DFUs, we explored whether radial extracorporeal shockwave therapy (rESWT) at the tibial circlularr osteotomy site (TOE) could enhance wound healing in rats. We found that TOE accelerated dorsal foot wound healing via small extracellular vesicles (sEV). This sEVs showed strong regenerative effects and modulated macrophage polarizations in vitro and in vivo. Single-cell sequencing revealed mesenchymal stem cells as the likely sEV source, with rESWT triggering sEV release through ATP/P2X7R/p38MAPK pathway. Proteomic analysis identified five differentially expressed proteins in sEVs, with Thbs1-enhanced sEVs enhancing wound healing by promoting IL4-induced M2 macrophage polarization. This innovative approach represents a promising alternative strategy for wound management, with potential for future DFU treatment.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE314229 | GEO | 2025/12/30

REPOSITORIES: GEO

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Project description:Diabetic foot ulcers (DFUs) are one of the major complications of diabetes. Its molecular pathology remains poorly understood, impeding the development of effective treatments. Although it has been established that multiple cell types, including fibroblasts, keratinocytes, macrophages and endothelial cells, all contribute to inhibition of healing, less is known regarding individual contributions of each cell type. Thus, we generated primary fibroblasts from non-healing DFUs and evaluated their cellular and molecular properties in comparison to non-diabetic foot fibroblasts (NFFs). Specifically, we analyzed both micro-RNA and mRNA expression profiles of primary DFU fibroblasts. These paired genomic analyses identified a total of 331 reciprocal miRNA-mRNA pairs (21 miRNAs (FC>2.0) along with 239 predicted target genes (FC>1.5) that are significantly and differentially expressed. Of these, we focused on three miRNAs (miR-21-5p, miR-34a-5p, miR-145-5p) found to be induced in DFU fibroblasts as most differentially regulated. Their involvement in cellular functions important for wound healing was investigated by testing the expression of their downstream targets as well as by quantifying cellular behaviors in a prospectively collected and generated cell lines from 15 patients (7 DFUF and 8 NFF samples). We found large number of downstream targets of miR-21-5p, miR-34a-5p, miR-145-5p to be coordinately regulated in mRNA profiles, which was confirmed by qPCR. Genomic analysis of miR-21-5p, miR-34a-5p, miR-145-5p and their target genes indicates that these are contributing to the inhibition of cell movement and cell proliferation, together with increased cell differentiation and senescence in DFU fibroblasts, which was confirmed by cellular assays. We conclude that induction of miR-21-5p, miR-34a-5p, miR-145-5p in DFU dermal fibroblasts plays an important role in impairing multiple cellular functions, thus contributing to overall inhibition of healing in DFUs.

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Early Radial Extracorporeal Shockwave Stimulation on Proximal Tibial Circular Osteotomy Site Enhanced Heterotopic Skin Wound Healing via Small Extracellular Vesicles

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