Chemical and Biomolecular Engineering, and The Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
Biomaterials. 2014 Jan;35(3):941-8. doi: 10.1016/j.biomaterials.2013.10.025. Epub 2013 Oct 27.
Stem cell differentiation is regulated by complex repertoires of signaling ligands which often use multivalent interactions, where multiple ligands tethered to one entity interact with multiple cellular receptors to yield oligomeric complexes. One such ligand is Sonic hedgehog (Shh), whose posttranslational lipid modifications and assembly into multimers enhance its biological potency, potentially through receptor clustering. Investigations of Shh typically utilize recombinant, monomeric protein, and thus the impact of multivalency on ligand potency is unexplored. Among its many activities, Shh is required for ventralization of the midbrain and forebrain and is therefore critical for the development of midbrain dopaminergic (mDA) and forebrain gamma-aminobutyric acid (GABA) inhibitory neurons. We have designed multivalent biomaterials presenting Shh in defined spatial arrangements and investigated the role of Shh valency in ventral specification of human embryonic stem cells (hESCs) into these therapeutically relevant cell types. Multivalent Shh conjugates with optimal valencies, compared to the monomeric Shh, increased the percentages of neurons belonging to mDA or forebrain GABAergic fates from 33% to 60% or 52% to 86%, respectively. Thus, multivalent Shh bioconjugates can enhance neuronal lineage commitment of pluripotent stem cells and thereby facilitate efficient derivation of neurons that could be used to treat Parkinson's and epilepsy patients.
干细胞分化受复杂的信号配体谱调控，这些配体通常采用多价相互作用，即将多个配体连接到一个实体上，与多个细胞受体相互作用，形成寡聚体复合物。其中一种配体是 Sonic hedgehog（Shh），其翻译后的脂质修饰和多聚体组装增强了其生物学效力，可能通过受体聚类实现。Shh 的研究通常利用重组的单体蛋白，因此多价性对配体效力的影响尚未得到探索。Shh 具有许多活性，其中之一是中脑和前脑的腹侧化，因此对于中脑多巴胺能（mDA）和前脑γ-氨基丁酸（GABA）抑制性神经元的发育至关重要。我们设计了呈现 Shh 特定空间排列的多价生物材料，并研究了 Shh 价态在人胚胎干细胞（hESC）向这些治疗相关细胞类型腹侧特化中的作用。与单体 Shh 相比，具有最佳价态的多价 Shh 缀合物分别将属于 mDA 或前脑 GABA 能命运的神经元百分比从 33%增加到 60%或从 52%增加到 86%。因此，多价 Shh 生物缀合物可以增强多能干细胞的神经元谱系承诺，从而促进可用于治疗帕金森病和癫痫患者的神经元的有效衍生。
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