Li Haoran, Chang Leslie, Du William W, Gupta Shaan, Khorshidi Azam, Sefton Michael, Yang Burton B
1] Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Mol Ther. 2014 Oct;22(10):1839-50. doi: 10.1038/mt.2014.115. Epub 2014 Jun 23.
Delayed or impaired wound healing is a major public health issue worldwide, especially in patients with diabetes mellitus and vascular atherosclerosis. MicroRNAs have been identified as key regulators of wound healing. Here, we show that miR-Pirate378a transgenic mice (and thus have inhibited miR-378a-5p function) display enhanced wound healing. Expression of vimentin and β3 integrin, two important modulators of wound healing, is markedly elevated in the transgenic mice. MiR-Pirate378a-transfected cells display greater mobility during migration assays, which was hypothesized to be due to the upregulation of vimentin and β3 integrin. Both molecules were confirmed to be targets of miR-378a, and thus their expression could be rescued by miR-Pirate378a. Overexpression of vimentin also contributed to fibroblast differentiation, and upregulation of β3 integrin was responsible for increased angiogenesis. Mice treatment with miR-Pirate378a-conjugated nanoparticles displayed enhanced wound healing. Thus, we have demonstrated that knockdown of miR-378a increased the expression of its target proteins, vimentin, and β3 integrin, which accelerated fibroblast migration and differentiation in vitro and enhanced wound healing in vivo.
伤口愈合延迟或受损是全球范围内的一个主要公共卫生问题，尤其是在糖尿病和血管动脉粥样硬化患者中。微小RNA已被确定为伤口愈合的关键调节因子。在此，我们表明miR-Pirate378a转基因小鼠（因此抑制了miR-378a-5p的功能）表现出增强的伤口愈合能力。波形蛋白和β3整合素这两种伤口愈合的重要调节因子在转基因小鼠中的表达显著升高。在迁移实验中，转染了miR-Pirate378a的细胞表现出更大的迁移能力，据推测这是由于波形蛋白和β3整合素的上调所致。这两种分子均被证实为miR-378a的靶标，因此它们的表达可被miR-Pirate378a挽救。波形蛋白的过表达也有助于成纤维细胞分化，而β3整合素的上调则导致血管生成增加。用miR-Pirate378a缀合的纳米颗粒处理的小鼠表现出增强的伤口愈合能力。因此，我们证明了敲低miR-378a可增加其靶蛋白波形蛋白和β3整合素的表达，这在体外加速了成纤维细胞的迁移和分化，并在体内增强了伤口愈合。
