Targeting S100A12 to Improve Angiogenesis and Accelerate Diabetic Wound Healing.

Long-term inflammation and impaired angiogenesis are thought to be the causes of delayed healing or nonhealing of diabetic wounds. S100A12 is an essential pro-inflammatory factor involved in inflammatory reactions and serves as a biomarker for various inflammatory diseases. However, whether high level of S100A12 exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that the serum concentration of S100A12 is significantly elevated in patients with type 2 diabetes. Exposure of stratified epidermal cells to high glucose environment led to increased expression and secretion of S100A12, resulting in impaired endothelial function by binding to the advanced glycation endproducts (RAGE) or Toll-like receptor 4 (TLR4) on endothelial cell. The transcription factor Krüpple-like Factor 5 (KLF5) is highly expressed in the epidermis under high glucose conditions, activating the transcriptional activity of the S100A12 and boost its expression. By establishing diabetic wounds model in alloxan-induced diabetic rabbit, we found that local inhibition of S100A12 significantly accelerated diabetic wound healing by promoting angiogenesis. Our results illustrated the novel endothelial-specific injury function of S100A12 in diabetic wounds and suggest that S100A12 is a potential target for the treatment of diabetic wounds.

Single-cell profiling reveals transcriptomic signatures of vascular endothelial cells in non-healing diabetic foot ulcers.

Background: The treatment of diabetic foot ulcers (DFUs) poses a challenging medical problem that has long plagued individuals with diabetes. Clinically, wounds that fail to heal for more than 12 weeks after the formation of DFUs are referred to as non-healing/chronic wounds. Among various factors contributing to the non-healing of DFUs, the impairment of skin microvascular endothelial cell function caused by high glucose plays a crucial role. Our study aimed to reveal the transcriptomic signatures of non-healing DFUs endothelial cells, providing novel intervention targets for treatment strategies. Methods: Based on the GEO dataset (GSE165816), we selected DFU-Healer, DFU-Non-healer, and healthy non-diabetic controls as research subjects. Single-cell RNA transcriptomic sequencing technology was employed to analyze the heterogeneity of endothelial cells in different skin tissue samples and identify healing-related endothelial cell subpopulations. Immunofluorescence was applied to validate the sequencing results on clinical specimens. Results: The number of endothelial cells and vascular density showed no significant differences among the three groups of skin specimens. However, endothelial cells from non-healing DFUs exhibited apparent inhibition of angiogenesis, inflammation, and immune-related signaling pathways. The expression of CCND1, ENO1, HIF1α, and SERPINE1 was significantly downregulated at the transcriptomic and histological levels. Further analysis demonstrated that healing-related endothelial cell subpopulations in non-healing DFUs has limited connection with other cell types and weaker differentiation ability. Conclusion: At the single-cell level, we uncovered the molecular and functional specificity of endothelial cells in non-healing DFUs and highlighted the importance of endothelial cell immune-mediated capability in angiogenesis and wound healing. This provides new insights for the treatment of DFUs.

Mechanical pressure-induced dedifferentiation of myofibroblasts inhibits scarring via SMYD3/ITGBL1 signaling.

Pressure therapy (PT) is an effective intervention for reducing scarring, but its underlying mechanism remains largely unclear. Here, we demonstrate that human scar-derived myofibroblasts dedifferentiate into normal fibroblasts in response to PT, and we identify how SMYD3/ITGBL1 contributes to the nuclear relay of mechanical signals. In clinical specimens, reductions in SMYD3 and ITGBL1 expression levels are strongly associated with the anti-scarring effects of PT. The integrin ß1/ILK pathway is inhibited in scar-derived myofibroblasts upon PT, leading to decreased TCF-4 and subsequently to reductions in SMYD3 expression, which reduces the levels of H3K4 trimethylation (H3K4me3) and further suppresses ITGBL1 expression, resulting the dedifferentiation of myofibroblasts into fibroblasts. In animal models, blocking SMYD3 expression results in reductions of scarring, mimicking the positive effects of PT. Our results show that SMYD3 and ITGBL1 act as sensors and mediators of mechanical pressure to inhibit the progression of fibrogenesis and provide therapeutic targets for fibrotic diseases.

The potential roles of circular RNAs as modulators in traumatic spinal cord injury.

Spinal cord injury (SCI) may cause long-term physical impairment and bring a substantial burden to both the individual patient and society. Existing therapeutic approaches for SCI have proven inadequate. This is mainly owing to the incomplete understanding of the cellular and molecular events post-injury. Circular RNAs (circRNAs) represent a new class of non-coding RNAs with a covalently closed annular structure that participates in regulating the transcription of certain genes and are linked to various biological processes and diseases. Mounting evidence is indicative that circRNAs are highly expressed in the spinal cord and they play key roles in multiple processes of neurological diseases. Recently, a role for circRNAs as effectors of SCI has emerged, leading to the continuity of relevant research. In this review, we presented current studies with regards to the abnormality of circRNAs mediating SCI by affecting mechanisms of autophagy, apoptosis, inflammation, and neural regeneration. Furthermore, the potential clinical value of circRNAs as therapeutic targets of SCI was also analyzed.