Multivalent ligands control stem cell behaviour in vitro and in vivo.
Multivalent ligands control stem cell behaviour in vitro and in vivo.
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DOI：
10.1038/nnano.2013.205
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发表时间：
2013-11
影响因子：
38.3
通讯作者：
中科院分区：
文献类型：
--
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设计可以与细胞相互作用并调节关键下游功能的纳米结构材料具有广泛的兴趣。特别是，具有纳米级特征的材料可以实现对多价相互作用的控制，多价相互作用涉及一个实体上的多个配体与另一个实体上的多个受体的同时结合，并且在整个生物学中普遍存在。在调节细胞功能和命运中起关键作用的生长因子和形态发生因子的细胞信号转导通常始于分泌的或细胞表面束缚的配体与靶细胞受体的这种多价结合，导致受体聚集。然而，协调配体-受体寡聚化的细胞机制是复杂的，并且控制多价相互作用从而调节生命系统内的关键信号传导事件的能力因此目前非常有限。在这里，我们展示了有效的多价缀合物的设计，可以组织成纳米级簇的干细胞受体和控制干细胞在体外和体内的行为。肝配蛋白-B2的胞外域，通常是一个完整的膜蛋白配体，被缀合到一个可溶性的生物聚合物，以产生多价的纳米级缀合物，有效地诱导神经干细胞中的信号传导，并促进他们的神经元分化，无论是在文化和大脑内。超分辨率显微镜分析产生了深入了解组织的受体-配体簇在纳米级。我们还发现，合成的多价偶联物肝配蛋白-B1强烈增强人胚胎和诱导多能干细胞分化为功能性多巴胺能神经元。因此，多价生物缀合物代表了用于在体外和体内控制靶干细胞的行为的强大工具和潜在的纳米级治疗剂。
There is broad interest in designing nanostructured materials that can interact with cells and regulate key downstream functions. In particular, materials with nanoscale features may enable control over multivalent interactions, which involve the simultaneous binding of multiple ligands on one entity to multiple receptors on another and are ubiquitous throughout biology. Cellular signal transduction of growth factor and morphogen cues that play critical roles in regulating cell function and fate often begins with such multivalent binding of ligands, either secreted or cell-surface tethered, to target cell receptors, leading to receptor clustering. Cellular mechanisms that orchestrate ligand-receptor oligomerisation are complex, however, and the capacity to control multivalent interactions and thereby modulate key signaling events within living systems is therefore currently very limited. Here we demonstrate the design of potent multivalent conjugates that can organise stem cell receptors into nanoscale clusters and control stem cell behaviour in vitro and in vivo. The ectodomain of ephrin-B2, normally an integral membrane protein ligand, was conjugated to a soluble biopolymer to yield multivalent nanoscale conjugates that potently induced signaling in neural stem cells and promoted their neuronal differentiation both in culture and within the brain. Super-resolution microscopy analysis yielded insights into the organisation of receptor-ligand clusters at the nanoscale. We also found that synthetic multivalent conjugates of ephrin-B1 strongly enhanced human embryonic and induced pluripotent stem cell differentiation into functional dopaminergic neurons. Multivalent bioconjugates thus represent powerful tools and potential nanoscale therapeutics for controlling the behaviour of target stem cells in vitro and in vivo.
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影响因子：
4.7
作者：
Pollock, Jacob F.;Ashton, Randolph S.;Healy, Kevin E.
通讯作者：
Healy, Kevin E.
影响因子：
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影响因子：
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作者：
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Sauer, Markus
影响因子：
38.3
作者：
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通讯作者：
Chan, Warren C. W.
影响因子：
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作者：
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通讯作者：
Freed WJ