Effects of cell-adhesive ligand presentation on pentapeptide supramolecular assembly and gelation: Simulations and Experiments
Effects of cell-adhesive ligand presentation on pentapeptide supramolecular assembly and gelation: Simulations and Experiments
复制标题
DOI：
10.1159/000534280
复制
发表时间：
2023-09-26
影响因子：
2.7
通讯作者：
Lampe，Kyle J.
中科院分区：
文献类型：
--
作者：
Thede，Andrew T.;Tang，James D.;Lampe，Kyle J.
细胞外基质（ECM）是一种复杂的，分层的材料，包含结构和生物活性成分。这种复杂性使得分离生物力学特性和细胞-基质相互作用的影响变得困难，特别是在3D环境中研究细胞过程时。基质力学和细胞粘附都是已知的特定细胞过程如干细胞增殖和分化的调节剂。然而，需要更多关于这些变量如何影响各种神经谱系的信息，这些神经谱系在移植后可以在治疗上改善中枢神经系统损伤或疾病后的神经功能。用于注射递送的快速组装五肽（RAPID）水凝胶是满足这些目标的一种生物材料方法，其由在生理介质中组装成物理水凝胶的肽序列家族组成。在这项研究中，我们研究了我们以前报道的超分子组装RAPID水凝胶功能化与ECM衍生的细胞粘附肽配体RGD，IKVAV，和YIGSR。使用分子动力学模拟和实验流变学，我们证明，这些整合素结合配体在生理浓度（3-12 μ < sc>m）没有影响组装的KYFIL肽系统。在模拟中，组装的分子测量，如氢键和π-π相互作用似乎不受细胞粘附序列或浓度的影响。聚类的可视化和溶剂可及表面积的分析表明，整合素结合结构域保持暴露。KYFIL或AYFIL水凝胶含有3 μ < sc>m的整合素结合结构域导致与其非官能化等同物一致的机械性能。这种用细胞粘附序列掺杂RAPID凝胶的策略允许精确调节肽配体浓度，而不依赖于流变学性质。RAPID水凝胶系统的可控性为研究整合素结合相互作用对包封的神经细胞的影响提供了机会，以辨别水凝胶微环境如何影响生长、成熟或分化。
The extracellular matrix (ECM) is a complex, hierarchical material containing structural and bioactive components. This complexity makes decoupling the effects of biomechanical properties and cell-matrix interactions difficult, especially when studying cellular processes in a 3D environment. Matrix mechanics and cell adhesion are both known regulators of specific cellular processes such as stem cell proliferation and differentiation. However, more information is required about how such variables impact various neural lineages that could, upon transplantation, therapeutically improve neural function after a central nervous system injury or disease. Rapidly Assembling Pentapeptides for Injectable Delivery (RAPID) hydrogels are one biomaterial approach to meet these goals, consisting of a family of peptide sequences that assemble into physical hydrogels in physiological media. In this study, we studied our previously reported supramolecularly-assembling RAPID hydrogels functionalized with the ECM-derived cell-adhesive peptide ligands RGD, IKVAV, and YIGSR. Using molecular dynamics simulations and experimental rheology, we demonstrated that these integrin-binding ligands at physiological concentrations (3–12 m< sc> m) did not impact the assembly of the KYFIL peptide system. In simulations, molecular measures of assembly such as hydrogen bonding and pi-pi interactions appeared unaffected by cell-adhesion sequence or concentration. Visualizations of clustering and analysis of solvent-accessible surface area indicated that the integrin-binding domains remained exposed. KYFIL or AYFIL hydrogels containing 3 m< sc> m of integrin-binding domains resulted in mechanical properties consistent with their non-functionalized equivalents. This strategy of doping RAPID gels with cell-adhesion sequences allows for the precise tuning of peptide ligand concentration, independent of the rheological properties. The controllability of the RAPID hydrogel system provides an opportunity to investigate the effect of integrin-binding interactions on encapsulated neural cells to discern how hydrogel microenvironment impacts growth, maturation, or differentiation.