Chemically Modified SDF-1α mRNA Promotes Random Flap Survival by Activating the SDF-1α/CXCR4 Axis in Rats

Abstract

Random skin flaps are frequently applied in plastic and reconstructive surgery for patients suffering from soft tissue defects caused by congenital deformities, trauma and tumor resection. However, ischemia and necrosis in distal parts of random skin flaps remains a common challenge that limits the clinical application of this procedure. Recently, chemically modified mRNA (modRNA) was found to have great therapeutic potential. Here, we explored the potential of fibroblasts engineered to express modified mRNAs encoding the stromal cell-derived factor-1α (SDF-1α) to improve vascularization and survival of therapeutic random skin flaps. Our study showed that fibroblasts pre-treated with SDF-1α modRNA have the potential to salvage ischemic skin flaps. Through a detailed analysis, we revealed that a fibroblast SDF-1α modRNA combinatorial treatment dramatically reduced tissue necrosis and significantly promoted neovascularization in random skin flaps compared to that in the control and vehicle groups. Moreover, SDF-1α modRNA transcription in fibroblasts promoted activation of the SDF-1α/CXCR4 pathway, with concomitant inactivation of the MEK/ERK, PI3K/AKT, and JAK2/STAT3 signaling pathways, indicating a possible correlation with cell proliferation and migration. Therefore, fibroblast-mediated SDF-1α modRNA expression represents a promising strategy for random skin flap regeneration.

Combination of chemically modified SDF‐1α mRNA and small skin improves wound healing in diabetic rats with full‐thickness skin defects

“…The 6 μl modRNA transfection system was found to possess a transfection effect with the extension of the transfection time in the first 24 h and reached the peak at 24 h, and then the fluorescence expression of GFP gradually decreased with time (Figure 2B). The result of this study was consistent with that of the previous experiment 11 . To detect the secreted SDF‐1α protein after transfection with SDF‐1α modRNA in Method 3, the ELISA was conducted immediately following transfection to determine the amount of SDF‐1α protein.…”

“…Nonetheless, following skin grafting a poorly vascularized wound bed can delay the wound healing 21 . In a previous study, combining modRNA with cell therapy and tissue engineering was found to be effective for achieving tissue regeneration 11,17 . However, it is still unknown as to whether the modRNA can be directly transfected into tissues rather than transfected into the cells using in tissue regeneration.…”

“…Several studies have demonstrated modRNA to highlight a new approach in treating ischemic disease 9,10 . A previous report has demonstrated that injecting SDF‐1α modRNA‐treated fibroblasts into the random skin flaps significantly improves the in vivo survival areas of the transplanted tissue by activating the SDF‐1α/CXCR4 axis pathway 11 . Although the cellular delivery of modRNA has been found to enhance protein expression and induce potent angiogenesis, the transfection process is relatively complicated, restricting the clinical application in the future.…”

Notoginseng Triterpenes Inhibited Autophagy in Random Flaps via the Beclin-1/VPS34/LC3 Signaling Pathway to Improve Tissue Survival

“…In the flap, the blood supply is maintained by the vascular network of the pedicle bed of the flap (Lorenzetti et al, 2001). When the flap's aspect ratio exceeds, the distal region of the flap will necrose due to insufficient blood supply to the microvascular network, which significantly limits randomness (Luo et al, 2021). Therefore, improving the vitality of random flaps and inhibiting necrosis are crucial for improving the clinical application of random flaps.…”

DataSheet1.ZIP

“…The random-pattern skin flap is a crucial tool for tissue reconstruction due to its simplicity, reliability, and convenience (Chen et al, 2021;Luo et al, 2021), which is particularly popular in plastic and reconstructive surgeries (Zhou et al, 2019). The microvascular network at the junction of the skin flap and tissue usually supports the survival of the skin flap with nutrition, which is prone to ischemia and necrosis due to insufficient blood supply at distal flaps (Wang et al, 2017).…”