利用牙髓干细胞及其内源性排列整齐的细胞外基质设计的无支架导管促进面神经再生。

Michelle D Drewry, Delin Shi, Matthew T Dailey, Kristi Rothermund, Sara Trbojevic, Alejandro J Almarza, Xinyan T Cui, Fatima N Syed-Picard
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摘要

目的:工程神经导管必须同时促进轴突再生和定向轴突延伸,才能有效恢复严重损伤的周围神经的功能。牙髓中含有内源性表达神经营养因子(NTFs)的干/祖细胞群,已知这些生长因子可诱导轴突修复。我们之前生成了由排列整齐的细胞外基质(ECM)组成的无支架牙髓干/祖细胞(DPSC)片。通过牙髓干/祖细胞(DPSC)固有的NTF表达和排列整齐的细胞外基质(ECM)的地形,这些薄片既能诱导轴突再生,又能引导轴突再生。在此,我们评估了利用这些排列整齐的 DPSC 片生成的生物活性导管在啮齿动物临界大小的神经损伤中恢复功能的能力:方法:将 DPSCs 培养在具有排列整齐的微槽的基底上,诱导细胞排列整齐并沉积排列整齐的 ECM,从而形成无支架神经导管。然后将薄片从基底上剥离并组装成无支架的圆柱形组织:体外分析证实,无支架 DPSC 导管保持了排列整齐的 ECM,并具有均匀分布的 NTF 表达。将排列整齐的 DPSC 导管植入大鼠面神经颊支的临界大小缺损处,可使损伤部位再生出类似束状神经的结构和有髓鞘的轴突延伸。此外,复合肌肉动作电位和刺激胡须运动测量显示,与临床治疗标准自体移植物相比,DPSC 导管治疗促进了相似的功能恢复:这项研究表明,无支架排列的DPSC导管可提供营养和引导线索,这是成功促进和引导轴突再生所需的关键设计要素。因此,这些导管能使神经损伤的功能恢复到与自体移植治疗相似的水平。这些导管为神经修复提供了一种新的生物活性方法,能够改善临床疗效和患者的生活质量。
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Enhancing facial nerve regeneration with scaffold-free conduits engineered using dental pulp stem cells and their endogenous, aligned extracellular matrix.

Objective. Engineered nerve conduits must simultaneously enhance axon regeneration and orient axon extension to effectively restore function of severely injured peripheral nerves. The dental pulp contains a population of stem/progenitor cells that endogenously express neurotrophic factors (NTFs), growth factors known to induce axon repair. We have previously generated scaffold-free dental pulp stem/progenitor cell (DPSC) sheets comprising an aligned extracellular matrix (ECM). Through the intrinsic NTF expression of DPSCs and the topography of the aligned ECM, these sheets both induce and guide axon regeneration. Here, the capacity of bioactive conduits generated using these aligned DPSC sheets to restore function in critical-sized nerve injuries in rodents was evaluated.Approach. Scaffold-free nerve conduits were formed by culturing DPSCs on a substrate with aligned microgrooves, inducing the cells to align and deposit an aligned ECM. The sheets were then detached from the substrate and assembled into scaffold-free cylindrical tissues.Main results. In vitroanalyses confirmed that scaffold-free DPSC conduits maintained an aligned ECM and had uniformly distributed NTF expression. Implanting the aligned DPSC conduits across critical-sized defects in the buccal branch of rat facial nerves resulted in the regeneration of a fascicular nerve-like structure and myelinated axon extension across the injury site. Furthermore, compound muscle action potential and stimulated whisker movement measurements revealed that the DPSC conduit treatment promoted similar functional recovery compared to the clinical standard of care, autografts. Significance. This study demonstrates that scaffold-free aligned DPSC conduits supply trophic and guidance cues, key design elements needed to successfully promote and orient axon regeneration. Consequently, these conduits restore function in nerve injuries to similar levels as autograft treatments. These conduits offer a novel bioactive approach to nerve repair capable of improving clinical outcomes and patient quality of life.

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