Institute for Women's Health, University College London, London, UK.
Mol Ther. 2010 Dec;18(12):2104-11. doi: 10.1038/mt.2010.174. Epub 2010 Aug 24.
The transforming growth factor-β (TGFβ) family plays a critical regulatory role in repair and coordination of remodeling after cutaneous wounding. TGFβ1-mediated chemotaxis promotes the recruitment of fibroblasts to the wound site and their resultant myofibroblastic transdifferentiation that is responsible for elastic fiber deposition and wound closure. TGFβ3 has been implicated in an antagonistic role regulating overt wound closure and promoting ordered dermal remodeling. We generated a mutant form of TGFβ3 (mutTGFβ3) by ablating its binding site for the latency-associated TGFβ binding protein (LTBP-1) in order to improve bioavailability and activity. The mutated cytokine is secreted as the stable latency-associated peptide (LAP)-associated form and is activated by normal intracellular and extracellular mechanisms including integrin-mediated activation but is not sequestered. We show localized intradermal transduction using a lentiviral vector expressing the mutTGFβ3 in a mouse skin wounding model reduced re-epithelialization density and fibroblast/myofibroblast transdifferentiation within the wound area, both indicative of reduced scar tissue formation.
转化生长因子-β（TGFβ）家族在皮肤创伤后的修复和重塑协调中发挥着关键的调节作用。TGFβ1 介导的趋化作用促进成纤维细胞向创伤部位募集，并促使其向肌成纤维细胞转化，从而负责弹性纤维的沉积和伤口闭合。TGFβ3 被认为在拮抗作用中调节明显的伤口闭合，并促进有序的真皮重塑。我们通过消除 TGFβ 结合蛋白（LTBP-1）的结合位点来生成 TGFβ3 的突变形式（mutTGFβ3），以提高其生物利用度和活性。突变细胞因子以稳定的潜伏相关肽（LAP）相关形式分泌，并通过正常的细胞内和细胞外机制（包括整合素介导的激活）被激活，但不会被隔离。我们在小鼠皮肤创伤模型中使用表达 mutTGFβ3 的慢病毒载体进行局部真皮转导，结果显示，在创伤区域内减少了再上皮化密度和纤维母细胞/肌成纤维细胞的转化，这表明减少了瘢痕组织的形成。
