Department of Bioengineering, Stanford University, Stanford, California 94305, USA.
Department of Materials Science & Engineering, Stanford University, Stanford, California 94305, USA.
Nat Mater. 2017 Dec;16(12):1233-1242. doi: 10.1038/nmat5020. Epub 2017 Oct 30.
Neural progenitor cell (NPC) culture within three-dimensional (3D) hydrogels is an attractive strategy for expanding a therapeutically relevant number of stem cells. However, relatively little is known about how 3D material properties such as stiffness and degradability affect the maintenance of NPC stemness in the absence of differentiation factors. Over a physiologically relevant range of stiffness from ∼0.5 to 50 kPa, stemness maintenance did not correlate with initial hydrogel stiffness. In contrast, hydrogel degradation was both correlated with, and necessary for, maintenance of NPC stemness. This requirement for degradation was independent of cytoskeletal tension generation and presentation of engineered adhesive ligands, instead relying on matrix remodelling to facilitate cadherin-mediated cell-cell contact and promote β-catenin signalling. In two additional hydrogel systems, permitting NPC-mediated matrix remodelling proved to be a generalizable strategy for stemness maintenance in 3D. Our findings have identified matrix remodelling, in the absence of cytoskeletal tension generation, as a previously unknown strategy to maintain stemness in 3D.
神经祖细胞（NPC）在三维（3D）水凝胶中的培养是扩大具有治疗相关性的干细胞数量的一种有吸引力的策略。然而，在没有分化因子的情况下，关于 3D 材料特性（如硬度和可降解性）如何影响 NPC 干性的维持，人们知之甚少。在从约 0.5 到 50kPa 的生理相关硬度范围内，干性维持与初始水凝胶硬度无关。相比之下，水凝胶的降解与 NPC 干性的维持相关且是必需的。这种降解的要求不依赖于细胞骨架张力的产生和工程化黏附配体的呈现，而是依赖于基质重塑来促进钙黏蛋白介导的细胞-细胞接触和促进β-连环蛋白信号传导。在另外两个水凝胶系统中，允许 NPC 介导的基质重塑被证明是在 3D 中维持干性的一种普遍适用的策略。我们的发现确定了在没有细胞骨架张力产生的情况下，基质重塑是维持 3D 干性的一个以前未知的策略。
