Matrix Remodeling Enhances the Differentiation Capacity of Neural Progenitor Cells in 3D Hydrogels
Matrix Remodeling Enhances the Differentiation Capacity of Neural Progenitor Cells in 3D Hydrogels
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DOI：
10.1002/advs.201801716
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发表时间：
2019-02-20
期刊：
影响因子：
15.1
通讯作者：
Heilshorn, Sarah C.
中科院分区：
文献类型：
--
作者：
Madl, Christopher M.;LeSavage, Bauer L.;Heilshorn, Sarah C.
神经祖细胞（Neural progenitor cells, npc）是修复受损神经组织的重要细胞来源。然而，扩大与治疗相关的npc数量并将其有效分化为所需的成熟细胞类型仍然是一个挑战。基于材料的策略，包括在3D水凝胶中培养，有可能克服这些限制。理想的材料能够同时支持NPC扩展和随后在单一平台上的差异化。最近有研究表明，细胞介导的3D水凝胶重塑对于维持NPC在扩张过程中的干细胞表型是必要的，但基质重塑在NPC分化和成熟中的作用尚不清楚。通过在易被NPC分泌的蛋白酶降解的工程蛋白水凝胶中培养NPC，研究人员发现，即使在高度可降解的凝胶中，也需要一定数量的重塑才能使NPC分化。经过足够的重塑时间后，化学诱导分化可分化为星形胶质细胞和神经递质反应神经元。基质重塑以钙粘蛋白依赖的方式调节转录共激活因子yes相关蛋白的表达，该蛋白驱动鼻咽癌干性因子的表达并维持鼻咽癌分化能力。因此，细胞可重塑水凝胶是一个有吸引力的平台，可以使NPCs扩增，然后将细胞分化为成熟的表型，用于治疗。
Neural progenitor cells (NPCs) are a promising cell source to repair damaged nervous tissue. However, expansion of therapeutically relevant numbers of NPCs and their efficient differentiation into desired mature cell types remains a challenge. Material-based strategies, including culture within 3D hydrogels, have the potential to overcome these current limitations. An ideal material would enable both NPC expansion and subsequent differentiation within a single platform. It has recently been demonstrated that cell-mediated remodeling of 3D hydrogels is necessary to maintain the stem cell phenotype of NPCs during expansion, but the role of matrix remodeling on NPC differentiation and maturation remains unknown. By culturing NPCs within engineered protein hydrogels susceptible to degradation by NPC-secreted proteases, it is identified that a critical amount of remodeling is necessary to enable NPC differentiation, even in highly degradable gels. Chemical induction of differentiation after sufficient remodeling time results in differentiation into astrocytes and neurotransmitter-responsive neurons. Matrix remodeling modulates expression of the transcriptional co-activator Yes-associated protein, which drives expression of NPC stemness factors and maintains NPC differentiation capacity, in a cadherin-dependent manner. Thus, cell-remodelable hydrogels are an attractive platform to enable expansion of NPCs followed by differentiation of the cells into mature phenotypes for therapeutic use.