Scheid Annette, Wenger Roland H, Schäffer Leonhard, Camenisch Isabelle, Distler Oliver, Ferenc Andrej, Cristina Heidi, Ryan Heather E, Johnson Randall S, Wagner Klaus F, Stauffer Urs G, Bauer Christian, Gassmann Max, Meuli Martin
Department of Surgery, University Children's Hospital of Zürich, Switzerland.
FASEB J. 2002 Mar;16(3):411-3. doi: 10.1096/fj.01-0496fje. Epub 2002 Jan 14.
In the first-trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar-limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in the sheep model in vivo and performed studies on the potential relevance of HIF-1alpha during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF-1alpha could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF-1alpha was expressed in fibroblasts and was markedly up-regulated at the wound edge. In scarring fetal wounds at GD120, HIF-1alpha was predominantly expressed in inflammatory cells. Expression of transforming growth factor beta3 (TGF-beta3), a potent antiscarring cytokine, overlapped with HIF-1a expression at GD100. HIF-1alpha-deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF-beta3, but not proscarring TGF-beta1, manifests hypoxia- and HIF-1alpha-dependent regulation. In conclusion, HIF-1alpha-dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.
在妊娠早期的哺乳动物胎儿中，皮肤伤口愈合时真皮结构能完美重建，不会形成瘢痕。了解胎儿伤口愈合过程中的环境分子调控，可能会揭示出预防产后瘢痕形成伤口修复的瘢痕限制治疗策略。因此，我们在绵羊体内模型中对胎儿皮肤氧合以及缺氧诱导因子1α（HIF-1α）在皮肤和伤口中的表达进行了研究，并在体外对HIF-1α在伤口愈合过程中的潜在相关性进行了研究。在整个正常发育过程中，皮肤氧分压水平处于低氧状态。在妊娠第60天（GD60）无瘢痕形成的胎儿皮肤中，无论是在健康组织还是受伤组织中均未检测到HIF-1α。在GD100时，在瘢痕形成最少的伤口中，HIF-1α在成纤维细胞中表达，并在伤口边缘明显上调。在GD120有瘢痕形成的胎儿伤口中，HIF-1α主要在炎症细胞中表达。转化生长因子β3（TGF-β3）是一种有效的抗瘢痕细胞因子，其表达在GD100时与HIF-1α的表达重叠。缺乏HIF-1α的小鼠胚胎成纤维细胞显示出迁移能力受损，并表明TGF-β3而非促瘢痕形成的TGF-β1表现出缺氧和HIF-1α依赖性调控。总之，HIF-1α依赖性调控一种有效的抗瘢痕细胞因子可能为伤口愈合的抗瘢痕处理提供新策略。
