Growth factors with enhanced syndecan binding generate tonic signalling and promote tissue healing.
Growth factors with enhanced syndecan binding generate tonic signalling and promote tissue healing.
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DOI：
10.1038/s41551-019-0469-1
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发表时间：
2020-04-01
影响因子：
28.1
通讯作者：
Martino, Mikael M
中科院分区：
文献类型：
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作者：
Mochizuki, Mayumi;Guc, Esra;Martino, Mikael M
生长因子可以刺激组织再生，但与次优递送系统相关的副作用和低有效性阻碍了它们在转化再生医学中的应用。生理上，生长因子与细胞外基质的相互作用控制其生物利用度和时空细胞信号传导。生长因子信号传导也通过与硫酸乙酰肝素蛋白聚糖（如多配体聚糖）结合在细胞表面水平上进行控制。在这里，我们表明，血管内皮生长因子-A（VEGF-A）和血小板衍生的生长因子-BB（PDGF-BB），被设计成具有syndecan结合序列触发持续的低强度信号（紧张性信号），并减少脱敏的生长因子受体。我们还表明，在小鼠模型中，强直信号导致上级形态发生活性，与syndecan结合的生长因子诱导更大的骨再生和伤口修复比野生型生长因子，以及减少肿瘤生长（与PDGF-BB的交付）和血管通透性（由VEGF-A触发）。通过多配体蛋白聚糖结合的紧张性信号传导也可以增强其他生长因子的再生能力。
Growth factors can stimulate tissue regeneration, but the side effects and low effectiveness associated with suboptimal delivery systems have impeded their use in translational regenerative medicine. Physiologically, growth factor interactions with the extracellular matrix control their bioavailability and spatiotemporal cellular signalling. Growth factor signalling is also controlled at the cell surface level via binding to heparan sulfate proteoglycans, such as syndecans. Here we show that vascular endothelial growth factor-A (VEGF-A) and platelet-derived growth factor-BB (PDGF-BB) that were engineered to have a syndecan-binding sequence trigger sustained low-intensity signalling (tonic signalling) and reduce the desensitization of growth factor receptors. We also show in mouse models that tonic signalling leads to superior morphogenetic activity, with syndecan-binding growth factors inducing greater bone regeneration and wound repair than wild-type growth factors, as well as reduced tumour growth (associated with PDGF-BB delivery) and vascular permeability (triggered by VEGF-A). Tonic signalling via syndecan binding may also enhance the regenerative capacity of other growth factors.