Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA.
Veterinary Specialty Center, Buffalo Grove, IL, USA.
Adv Exp Med Biol. 2018;1119:41-71. doi: 10.1007/5584_2018_254.
Peripheral nerve injuries (PNI) occur as the result of sudden trauma and can lead to life-long disability, reduced quality of life, and heavy economic and social burdens. Although the peripheral nervous system (PNS) has the intrinsic capacity to regenerate and regrow axons to a certain extent, current treatments frequently show incomplete recovery with poor functional outcomes, particularly for large PNI. Many surgical procedures are available to halt the propagation of nerve damage, and the choice of a procedure depends on the extent of the injury. In particular, recovery from large PNI gaps is difficult to achieve without any therapeutic intervention or some form of tissue/cell-based therapy. Autologous nerve grafting, considered the "gold standard" is often implemented for treatment of gap formation type PNI. Although these surgical procedures provide many benefits, there are still considerable limitations associated with such procedures as donor site morbidity, neuroma formation, fascicle mismatch, and scarring. To overcome such restrictions, researchers have explored various avenues to improve post-surgical outcomes. The most commonly studied methods include: cell transplantation, growth factor delivery to stimulate regenerating axons and implanting nerve guidance conduits containing replacement cells at the site of injury. Replacement cells which offer maximum benefits for the treatment of PNI, are Schwann cells (SCs), which are the peripheral glial cells and in part responsible for clearing out debris from the site of injury. Additionally, they release growth factors to stimulate myelination and axonal regeneration. Both primary SCs and genetically modified SCs enhance nerve regeneration in animal models; however, there is no good source for extracting SCs and the only method to obtain SCs is by sacrificing a healthy nerve. To overcome such challenges, various cell types have been investigated and reported to enhance nerve regeneration.In this review, we have focused on cell-based strategies aimed to enhance peripheral nerve regeneration, in particular the use of mesenchymal stem cells (MSCs). Mesenchymal stem cells are preferred due to benefits such as autologous transplantation, routine isolation procedures, and paracrine and immunomodulatory properties. Mesenchymal stem cells have been transplanted at the site of injury either directly in their native form (undifferentiated) or in a SC-like form (transdifferentiated) and have been shown to significantly enhance nerve regeneration. In addition to transdifferentiated MSCs, some studies have also transplanted ex-vivo genetically modified MSCs that hypersecrete growth factors to improve neuroregeneration.
周围神经损伤 (PNI) 是由突然的创伤引起的，可导致终身残疾、生活质量下降以及沉重的经济和社会负担。尽管周围神经系统 (PNS) 具有一定程度的内在再生和轴突再生能力，但目前的治疗方法常常显示出不完全恢复和功能结果不佳，尤其是对于大的 PNI。有许多手术程序可用于阻止神经损伤的传播，而手术程序的选择取决于损伤的程度。特别是，没有任何治疗干预或某种形式的组织/细胞治疗，很难从大的 PNI 间隙中恢复。自体神经移植被认为是“金标准”，常用于治疗间隙形成型 PNI。尽管这些手术程序提供了许多好处，但与这些程序相关的仍然存在相当大的局限性，例如供体部位发病率、神经瘤形成、束匹配不良和瘢痕形成。为了克服这些限制，研究人员已经探索了各种途径来改善手术后的结果。最常研究的方法包括：细胞移植、生长因子递送来刺激再生轴突和在损伤部位植入含有替代细胞的神经引导导管。用于治疗 PNI 的替代细胞中，雪旺细胞 (SCs) 提供了最大的益处，SCs 是周围神经胶质细胞，部分负责清除损伤部位的碎片。此外，它们释放生长因子来刺激髓鞘形成和轴突再生。在动物模型中，原代 SCs 和基因修饰的 SCs 均增强了神经再生；然而，没有良好的提取 SCs 的来源，获得 SCs 的唯一方法是牺牲健康的神经。为了克服这些挑战，已经研究并报道了各种细胞类型以增强神经再生。在这篇综述中，我们重点介绍了旨在增强周围神经再生的基于细胞的策略，特别是使用间充质干细胞 (MSCs)。间充质干细胞因其具有自体移植、常规分离程序以及旁分泌和免疫调节特性等优点而被优先选择。间充质干细胞已直接以其天然形式（未分化）或 SC 样形式（转分化）移植到损伤部位，并已显示出可显著增强神经再生。除了转分化的 MSC 之外，一些研究还移植了外源性基因修饰的 MSC，这些 MSC 过度分泌生长因子以改善神经再生。
