Dental Pulp Cell Sheets Enhance Facial Nerve Regeneration via Local Neurotrophic Factor Delivery
Dental Pulp Cell Sheets Enhance Facial Nerve Regeneration via Local Neurotrophic Factor Delivery
复制标题
DOI：
10.1089/ten.tea.2020.0265
复制
发表时间：
2020-12-21
影响因子：
4.1
通讯作者：
Syed-Picard, Fatima N.
中科院分区：
文献类型：
--
作者：
Ahmed, Meer N.;Shi, Delin;Syed-Picard, Fatima N.
影响声明目前周围神经损伤（PNI）治疗的主要挑战是修复时间延长和功能恢复不足。牙髓干/祖细胞（DPC）是已知的内源性表达高水平的神经营养因子（NTFs），生长因子，促进轴突再生。在这项研究中，我们证明，无支架DPC片可以作为有效的载体系统，以促进NTF生产DPC的交付和保留到PNI的网站，并改善功能性神经再生。DPC片具有很高的翻译可行性，可以增加目前的护理标准，以提高生活质量的患者处理PNIs.A持续的神经营养因子（NTF）交付到周围神经损伤（PNI）的网站的有效策略将加速愈合和增强功能恢复，解决与目前的护理标准相关的主要临床挑战。在这项研究中，无支架细胞片使用人牙髓干/祖细胞，内源性表达高水平的NTFs，作为生物活性的NTF输送系统的使用。此外，评价了成纤维细胞生长因子2（FGF 2）对牙髓细胞（DPC）片表达NTF的影响。体外分析证实，DPC片表达高水平的NTF信使RNA（mRNA）和蛋白质，并且向DPC片培养物中添加FGF 2通过显著增加片的细胞性来增加总NTF产生。此外，DPC片分泌体刺激培养的神经元细胞中的神经突形成和延伸，并且当DPC片与FGF 2一起培养时，这些功能效应进一步增强。这些神经突发生的结果被NTF抑制逆转，证实DPC片通过产生NTF对神经元细胞活性具有积极作用。在大鼠面神经挤压损伤模型中对DPC片的进一步体内评价确定，与未处理的对照相比，用DPC片处理的神经具有通过损伤部位的更大轴突再生和上级功能恢复，如通过复合肌肉动作电位测量定量评估的。这项研究表明，使用DPC片材作为NTF递送的载体，可以增强目前治疗PNI的方法，以加速再生并增强功能结果。
Impact statementThe major challenges associated with current treatments of peripheral nerve injuries (PNIs) are prolonged repair times and insufficient functional recovery. Dental pulp stem/progenitor cells (DPCs) are known to endogenously express high levels of neurotrophic factors (NTFs), growth factors that enhance axon regeneration. In this study, we demonstrate that scaffold-free DPC sheets can act as effective carrier systems to facilitate the delivery and retention of NTF-producing DPCs to sites of PNIs and improve functional nerve regeneration. DPC sheets have high translational feasibility and could augment the current standard of care to enhance the quality of life for patients dealing with PNIs.An effective strategy for sustained neurotrophic factor (NTF) delivery to sites of peripheral nerve injury (PNI) would accelerate healing and enhance functional recovery, addressing the major clinical challenges associated with the current standard of care. In this study, scaffold-free cell sheets were generated using human dental pulp stem/progenitor cells, that endogenously express high levels of NTFs, for use as bioactive NTF delivery systems. Additionally, the effect of fibroblast growth factor 2 (FGF2) on NTF expression by dental pulp cell (DPC) sheets was evaluated. In vitro analysis confirmed that DPC sheets express high levels of NTF messenger RNA (mRNA) and proteins, and the addition of FGF2 to DPC sheet culture increased total NTF production by significantly increasing the cellularity of sheets. Furthermore, the DPC sheet secretome stimulated neurite formation and extension in cultured neuronal cells, and these functional effects were further enhanced when DPC sheets were cultured with FGF2. These neuritogenic results were reversed by NTF inhibition substantiating that DPC sheets have a positive effect on neuronal cell activity through the production of NTFs. Further evaluation of DPC sheets in a rat facial nerve crush injury model in vivo established that in comparison with untreated controls, nerves treated with DPC sheets had greater axon regeneration through the injury site and superior functional recovery as quantitatively assessed by compound muscle action potential measurements. This study demonstrates the use of DPC sheets as vehicles for NTF delivery that could augment the current methods for treating PNIs to accelerate regeneration and enhance the functional outcome.