Elucidating the mechanobiology of malignant brain tumors using a brain matrix-mimetic hyaluronic acid hydrogel platform.
Elucidating the mechanobiology of malignant brain tumors using a brain matrix-mimetic hyaluronic acid hydrogel platform.
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DOI：
10.1016/j.biomaterials.2011.07.005
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发表时间：
2011-11
期刊：
影响因子：
14
通讯作者：
Kumar, Sanjay
中科院分区：
文献类型：
--
作者：
Ananthanarayanan, Badriprasad;Kim, Yushan;Kumar, Sanjay
多形性胶质母细胞瘤（GBM）是一种以单细胞弥漫性浸润到脑实质为特征的恶性脑肿瘤，这一过程部分依赖于肿瘤细胞与脑细胞外基质（ECM）之间异常的生化和生物物理相互作用。理解脑外基质调控GBM侵袭的一个主要障碍是缺乏模型基质系统，该系统可以概括脑外基质的独特组成和物理结构，同时允许独立控制粘附配体密度、力学和微观结构。为了满足这一需求，我们合成了基于透明质酸（HA）的模拟脑外基质，其硬度范围包括正常脑组织和致瘤脑组织，并用短Arg-Gly-Asp （RGD）肽对这些材料进行功能化，以促进细胞粘附。扫描电镜显示，水凝胶具有致密的片状微观结构，具有明显的纳米级孔隙，类似于脑细胞外空间。在平面水凝胶基质上，随着RGD肽密度的增加，胶质瘤细胞扩散面积和肌动蛋白应力纤维组装量明显增加。在RGD密度不变的情况下，增加HA刚度也产生了类似的趋势，增加了随机运动的速度。在三维（3D）球体范式中，胶质瘤细胞侵入透明质酸水凝胶，其形态模式与在平面或3D胶原基ecm中观察到的形态模式不同，但与脑切片中观察到的形态模式高度相似。该材料系统代表了一种具有可调配体密度和刚度的脑模拟模型ECM，可用于脑肿瘤进展的机械生物学调节研究。
Glioblastoma multiforme (GBM) is a malignant brain tumor characterized by diffuse infiltration of single cells into the brain parenchyma, which is a process that relies in part on aberrant biochemical and biophysical interactions between tumor cells and the brain extracellular matrix (ECM). A major obstacle to understanding ECM regulation of GBM invasion is the absence of model matrix systems that recapitulate the distinct composition and physical structure of brain ECM while allowing independent control of adhesive ligand density, mechanics, and microstructure. To address this need, we synthesized brain-mimetic ECMs based on hyaluronic acid (HA) with a range of stiffnesses that encompasses normal and tumorigenic brain tissue and functionalized these materials with short Arg-Gly-Asp (RGD) peptides to facilitate cell adhesion. Scanning electron micrographs of the hydrogels revealed a dense, sheet-like microstructure with apparent nanoscale porosity similar to brain extracellular space. On flat hydrogel substrates, glioma cell spreading area and actin stress fiber assembly increased strongly with increasing density of RGD peptide. Increasing HA stiffness under constant RGD density produced similar trends and increased the speed of random motility. In a three-dimensional (3D) spheroid paradigm, glioma cells invaded HA hydrogels with morphological patterns distinct from those observed on flat surfaces or in 3D collagen-based ECMs but highly reminiscent of those seen in brain slices. This material system represents a brain-mimetic model ECM with tunable ligand density and stiffness amenable to investigations of the mechanobiological regulation of brain tumor progression.
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