Poon Raymond, Nik Saeid Amini, Ahn Jessica, Slade Laura, Alman Benjamin A
Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
BMC Cell Biol. 2009 May 11;10:38. doi: 10.1186/1471-2121-10-38.
beta-catenin and transforming growth factor beta signaling are activated in fibroblasts during wound healing. Both signaling pathways positively regulate fibroblast proliferation during this reparative process, and the effect of transforming growth factor beta is partially mediated by beta-catenin. Other cellular processes, such as cell motility and the induction of extracellular matrix contraction, also play important roles during wound repair. We examined the function of beta-catenin and its interaction with transforming growth factor beta in cell motility and the induction of collagen lattice contraction.
Floating three dimensional collagen lattices seeded with cells expressing conditional null and stabilized beta-catenin alleles, showed a modest negative relationship between beta-catenin level and the degree of lattice contraction. Transforming growth factor beta had a more dramatic effect, positively regulating lattice contraction. In contrast to the situation in the regulation of cell proliferation, this effect of transforming growth factor beta was not mediated by beta-catenin. Treating wild-type cells or primary human fibroblasts with dickkopf-1, which inhibits beta-catenin, or lithium, which stimulates beta-catenin produced similar results. Scratch wound assays and Boyden chamber motility studies using these same cells found that beta-catenin positively regulated cell motility, while transforming growth factor beta had little effect.
This data demonstrates the complexity of the interaction of various signaling pathways in the regulation of cell behavior during wound repair. Cell motility and the induction of collagen lattice contraction are not always coupled, and are likely regulated by different intracellular mechanisms. There is unlikely to be a single signaling pathway that acts as master regulator of fibroblast behavior in wound repair. beta-catenin plays dominant role regulating cell motility, while transforming growth factor beta plays a dominant role regulating the induction of collagen lattice contraction.
在伤口愈合过程中，β-连环蛋白和转化生长因子β信号通路在成纤维细胞中被激活。在这个修复过程中，这两条信号通路均正向调节成纤维细胞的增殖，并且转化生长因子β的作用部分由β-连环蛋白介导。其他细胞过程，如细胞运动和细胞外基质收缩的诱导，在伤口修复过程中也发挥着重要作用。我们研究了β-连环蛋白的功能及其在细胞运动和胶原晶格收缩诱导中与转化生长因子β的相互作用。
接种表达条件性缺失和稳定化β-连环蛋白等位基因的细胞的漂浮三维胶原晶格显示，β-连环蛋白水平与晶格收缩程度之间存在适度的负相关关系。转化生长因子β具有更显著的作用，正向调节晶格收缩。与细胞增殖调节的情况不同，转化生长因子β的这种作用不是由β-连环蛋白介导的。用抑制β-连环蛋白的迪克kopf-1或刺激β-连环蛋白的锂处理野生型细胞或原代人成纤维细胞产生了相似的结果。使用这些相同细胞进行的划痕伤口试验和博伊登室运动性研究发现，β-连环蛋白正向调节细胞运动，而转化生长因子β的作用很小。
这些数据证明了在伤口修复过程中调节细胞行为时各种信号通路相互作用的复杂性。细胞运动和胶原晶格收缩的诱导并不总是相关联的，并且可能由不同的细胞内机制调节。不太可能存在单一的信号通路作为伤口修复中调节成纤维细胞行为的主要调节因子。β-连环蛋白在调节细胞运动中起主导作用，而转化生长因子β在调节胶原晶格收缩的诱导中起主导作用。
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