Growth Factors Engineered for Super-Affinity to the Extracellular Matrix Enhance Tissue Healing
Growth Factors Engineered for Super-Affinity to the Extracellular Matrix Enhance Tissue Healing
复制标题
DOI：
10.1126/science.1247663
复制
发表时间：
2014-02-21
期刊：
影响因子：
56.9
通讯作者：
Hubbell, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Martino, Mikael M.;Briquez, Priscilla S.;Hubbell, Jeffrey A.
生长因子（GFs）在组织修复中起着至关重要的作用，但它们在临床应用中的转化一直不大。生理上，GF与细胞外基质（ECM）组分的相互作用促进了局部和空间调节的信号传导；因此，我们推断在临床使用的形式中缺乏ECM结合可能是有限翻译的基础。我们发现胎盘生长因子-2（PlGF-2(123-144)）中的一个结构域异常强烈且混杂地与ECM蛋白结合。通过将该结构域融合到GF的血管内皮生长因子-a、血小板衍生生长因子- bb和骨形态发生蛋白-2中，我们生成了与ECM具有超亲和力的工程GF变体。与野生型GFs相比，这些ECM超亲和性GFs诱导啮齿动物慢性伤口和骨缺损模型的修复能力大大增强，表明这种方法可能在几种再生医学应用中有用。
Growth factors (GFs) are critical in tissue repair, but their translation to clinical use has been modest. Physiologically, GF interactions with extracellular matrix (ECM) components facilitate localized and spatially regulated signaling; therefore, we reasoned that the lack of ECM binding in their clinically used forms could underlie the limited translation. We discovered that a domain in placenta growth factor-2 (PlGF-2(123-144)) binds exceptionally strongly and promiscuously to ECM proteins. By fusing this domain to the GFs vascular endothelial growth factor-A, platelet-derived growth factor-BB, and bone morphogenetic protein-2, we generated engineered GF variants with super-affinity to the ECM. These ECM super-affinity GFs induced repair in rodent models of chronic wounds and bone defects that was greatly enhanced as compared to treatment with the wild-type GFs, demonstrating that this approach may be useful in several regenerative medicine applications.