Mace Kimberly A, Hansen Scott L, Myers Connie, Young David M, Boudreau Nancy
Surgical Research Laboratory, Department of Surgery, University of California San Francisco, San Francisco General Hospital, CA 94110, USA.
J Cell Sci. 2005 Jun 15;118(Pt 12):2567-77. doi: 10.1242/jcs.02399. Epub 2005 May 24.
Wound repair requires both the recruitment and coordination of numerous cell types including inflammatory cells, fibroblasts, endothelial and epithelial cells. Each cell type has a distinct set of cell behavior such as formation of granulation tissue and basement membrane, migration, proliferation and redifferentiation. These processes are dependent on cell-cell and cell-ECM signaling, intracellular signal transduction cascades, and ultimately, changes in gene transcription. We have investigated the role of the transcription factor HOXA3 in wound repair and angiogenesis. Here we show that HOXA3 increases endothelial cell migration, induces angiogenesis in vivo, and leads to increased expression of the matrix metalloproteinase-14 (MMP-14) and urokinase-type plasminogen activator receptor (uPAR) genes in endothelial cells in culture and in vivo in response to injury. We find that HOXA3 gene expression is upregulated during wound healing in angiogenic endothelial cells and keratinocytes, and that HOXA3 is not induced in genetically diabetic mice that have impaired angiogenesis and wound repair. We demonstrate that gene transfer of HOXA3 into diabetic mouse wounds leads to dramatic improvements in both angiogenesis and wound closure. In addition, we show that HOXA3 promotes migration of endothelial cells and keratinocytes in a uPAR-dependent manner. Together these findings illustrate how the morphoregulatory protein, HOXA3 can facilitate tissue remodeling via coordinated changes in both epithelial and endothelial cell gene expression and behavior in adult tissues during wound repair.
伤口修复需要募集和协调多种细胞类型，包括炎性细胞、成纤维细胞、内皮细胞和上皮细胞。每种细胞类型都有一组独特的细胞行为，如形成肉芽组织和基底膜、迁移、增殖和再分化。这些过程依赖于细胞 - 细胞和细胞 - 细胞外基质信号传导、细胞内信号转导级联反应，最终依赖于基因转录的变化。我们研究了转录因子HOXA3在伤口修复和血管生成中的作用。在此我们表明，HOXA3可增加内皮细胞迁移，在体内诱导血管生成，并导致培养的内皮细胞以及体内损伤后的内皮细胞中基质金属蛋白酶 - 14（MMP - 14）和尿激酶型纤溶酶原激活剂受体（uPAR）基因的表达增加。我们发现，在血管生成的内皮细胞和角质形成细胞的伤口愈合过程中，HOXA3基因表达上调，而在血管生成和伤口修复受损的遗传性糖尿病小鼠中，HOXA3未被诱导。我们证明，将HOXA3基因转移到糖尿病小鼠伤口中可显著改善血管生成和伤口闭合。此外，我们表明HOXA3以uPAR依赖的方式促进内皮细胞和角质形成细胞的迁移。这些发现共同说明了形态调节蛋白HOXA3如何通过成年组织伤口修复过程中上皮细胞和内皮细胞基因表达及行为的协调变化来促进组织重塑。
