Application and potential of stem cells in the repair of facial nerve injury

doi:10.3969/j.issn.2095-4344.1724

Abstract

Abstract:

BACKGROUND: Facial nerve injury is extremely common, and autologous nerve transplantation as its “gold standard” treatment has limitations. Therefore, stem cell therapy for facial nerve injury has become a hot topic in recent years.
OBJECTIVE: To elaborate the progress in basic experiments of stem cells in the repair of facial nerve injury, by describing the characteristics and applications of experimental animal models, tissue engineering and various stem cells.
METHODS: PubMed, CNKI, and WanFang databases were retrieved for relevant articles published from 2005 to 2018. The keywords were “stem cell, tissue engineering, facial nerve” in Chinese and English. Literature regarding relevant experimental research and reviews was searched, and finally 54 articles were included.
RESULTS AND CONCLUSION: Stem cells used in facial nerve injury repair mainly include neural stem cells, bone marrow mesenchymal stem cells, adipose stem cells, odontogenic stem cells, skeletal muscle stem cells, and olfactory stem cells, which are characterized by various types, wide sources, rapid proliferation and multi-directional differentiation. Stem cell therapy has great potential to replace autologous nerve transplantation and become the main treatment for facial nerve injury in the future.

Key words: neural stem cells, bone marrow mesenchymal stem cells, adipose-derived stem cells, odontogenic stem cells, skeletal muscle stem cells, olfactory stem cells, facial nerve injury, alternative therapy

CLC Number:

Xiao Guangqing, Lun Zhigang, Chen Huizhen, Li Aimin. Application and potential of stem cells in the repair of facial nerve injury[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(21): 3439-3444.

Figures/Tables 3

2.3 各类干细胞的特点及其在面神经损伤修复中的相关研究 2.3.1 影响干细胞移植修复面神经损伤的因素干细胞修复面神经损伤是一个既复杂又漫长的过程，在移植过程中，有许多因素可以影响面神经的再生[11]，包括损伤的部位和程度、干细胞移植的时间窗、干细胞的分化状态等都会影响其效果。另外，各种神经营养因子如脑源性神经营养因子、神经营养因子3、胶质细胞源性神经营养因子和睫状神经营养因子等也可以改善干细胞修复面神经损伤的效果，还有研究表明富血小板血浆也可以促进干细胞对面神经损伤的修复效果[12]。总之，组织工程与干细胞联合应用修复面神经损伤具有较好的发展前景[13]。 2.3.2 神经干细胞胚胎期哺乳动物神经干细胞主要分布于海马、脑室下区、纹状体和皮质，成年哺乳动物神经干细胞主要分布于侧脑室的下室区和海马齿状回的颗粒下层[14-15]。神经干细胞在面神经修复中的应用是许多研究的重点，其可以分化成为神经元、星形胶质细胞和少突胶质细胞[16]，在特定的条件下也可以诱导分化为许旺细胞[17]。神经干细胞移植具有可塑性强、高迁移率和低免疫原性等优点，但其需要在哺乳动物的大脑内取材，来源相对局限，因此在临床试验中开展相对较难，临床研究应用价值有限。Guo等[18]用含有胶原蛋白、神经生长因子和神经干细胞的壳聚糖导管移植治疗家兔面神经10 mm缺损，移植12周后进行电生理、组织学、免疫组织化学检测，其修复面神经再生效果明显优于不含神经干细胞的对照组，并且与自体神经移植组效果相似，证实了神经干细胞可以作为面神经损伤修复的种子细胞。Shi等[19]利用表达胶质细胞源性神经营养因子基因的慢病毒转染神经干细胞，转染后的神经干细胞与聚乙醇酸导管复合移植治疗大鼠面神经横断损伤，12周后进行电生理、免疫组织化学染色和神经形态学分析，结果发现胶质细胞源性神经营养因子转染神经干细胞可以明显提高再生神经轴突的数量，对面神经损伤修复的效果优于未转染神经干细胞，该研究表明，神经干细胞可以促进面神经损伤的修复，胶质细胞源性神经营养因子可以提高神经干细胞对神经损伤的修复效果。 2.3.3 骨髓间充质干细胞骨髓间充质干细胞是一类存在于骨髓中且具有高度自我更新和多向分化潜能的干细胞，在体内或体外特定的诱导条件下，可以向脂肪、骨、肌肉及神经等多种组织细胞分化，也可以诱导分化为许旺细胞表型细胞，支持神经再生，其特性与许旺细胞很相似[20]。与神经干细胞相比，骨髓间充质干细胞的增殖分化能力相对较低，但其来源于骨髓，更易获得，取材相对方便，移植后不良反应小，在传代多次后仍然具有干细胞的特性[21]，其缺点是采集过程具有侵入性和痛苦性，同时细胞增殖能力受供者年龄的影响，但骨髓间充质干细胞仍然是目前用于面神经损伤研究的重要种子细胞。Wang等[22]以自体静脉导管为支架将骨髓间充质干细胞和转分化后具有许旺细胞表型的骨髓间充质干细胞移植到家兔1 cm面神经缺损模型中，4周后进行行为学、免疫组织化学以及形态学检查分析，结果发现移植具有许旺细胞表型的骨髓间充质干细胞组家兔面神经损伤部位更早地出现神经元以及更多数量的髓鞘轴突，8周后利用RT-PCR技术检测发现具有许旺细胞表型的骨髓间充质干细胞组家兔面神经损伤部位的髓鞘蛋白mRNA水平高于骨髓间充质干细胞组，该研究表明，与正常的骨髓间充质干细胞相比，具有许旺表型的骨髓间充质干细胞可以加速横断神经轴突再生，达到更好的修复效果。Costa等[23]将骨髓间充质干细胞或分化后具有许旺细胞表型的骨髓间充质干细胞联合自体神经填充的聚乙醇酸导管移植到大鼠面神经下颌支损伤模型中，6周后进行轴突形态测量和复合肌肉动作电位分析，发现骨髓间充质干细胞组和具有许旺表型的骨髓间充质干细胞组面神经轴突数量以及动作电位振幅均优于未移植细胞组，且具有许旺表型的骨髓间充质干细胞对损伤神经的修复效果优于骨髓间充质干细胞。 2.3.4 脂肪干细胞脂肪干细胞来源于脂肪组织，是相对于骨髓间充质干细胞来说具有更高增殖和分化潜力的干细胞[24]，在一定条件下可以分化成许多有特定功能的细胞。因哺乳动物体内脂肪含量丰富，可以通过微创手术获得，便于提取，因此脂肪干细胞具有侵入性小、来源相对广泛等特点，适合用于自体移植，与骨髓间充质干细胞一样，脂肪干细胞也可以分化为具有许旺细胞表型细胞，同样具有移植后不良反应小的特点，同时脂肪干细胞可以释放许多生长因子，促进内源性许旺细胞的聚集[25]，有利于神经的修复和再生；缺点是脂肪干细胞的活性受来源部位、脂肪层以及供者年龄的影响[26]。在面神经乃至整个神经系统领域中，脂肪干细胞都具有极大的研究价值，也是目前常用于面神经损伤修复研究的种子细胞之一。Ghoreishian等[27]将来源于混种狗自体脂肪干细胞填充于聚四氟乙烯管并用藻酸盐水凝胶固定，移植修复狗7 mm面神经缺损，12周后发现实验组轴突数量、神经传导速度和神经动作电位的最大振幅明显高于对照组，证实脂肪干细胞可以从功能的角度促进损伤面神经的恢复。Watanabe等[28]将未分化的脂肪干细胞、分化的脂肪干细胞以及许旺细胞植入胶原凝胶中，修复7 mm大鼠面神经缺损，13周后经形态学定量分析发现3组大鼠面神经功能恢复接近自体神经移植，该研究表明3种细胞具有类似的神经再生潜力。Kamei等[29]利用脂肪干细胞联合聚乙醇酸导管通过介入跳跃移植技术将大鼠夹闭损伤的面神经主干与同侧舌下神经连接起来，术后13周进行生理学和组织病理学评估，结果发现面神经主干与同侧舌下神经之间的导管内出现神经再生且脂肪干细胞对神经的再生具有促进作用，所有治疗组都显示出再生的神经纤维，由舌下神经核和面神经核双重支配，该研究成果表明，脂肪干细胞联合聚乙醇酸导管可以促进神经再生，介入跳跃移植技术也是一种可以用于修复神经损伤的方法。 2.3.5 牙源性干细胞牙源性干细胞具有类似间充质干细胞的特性，包括自我更新和多向分化潜能。牙源性干细胞包括牙髓干细胞[30]、牙龈间充质干细胞、来自人体脱落乳牙的干细胞、来自根尖乳头的干细胞和牙周韧带干细胞等[31]。牙源性干细胞来源于牙周组织，资源丰富，临床应用潜力大，除了具有高度自我更新和多向分化特性外，还具有易获得性和侵入性小等优点。在特定刺激的存在下，牙源性干细胞可以分化为成骨细胞[32]、脂肪细胞和肌原细胞等各种细胞类型。Sasaki等[33]将嵌入胶原凝胶中的牙髓干细胞联合聚乳酸管移植到大鼠面神经颊支7 mm损伤模型中，移植5 d后免疫荧光染色发现聚乳酸管中出现轴突再生，移植9周后免疫荧光染色检测发现再生神经中出现大量轴突，证实了牙髓干细胞联合聚乳酸管的应用可以促进神经再生。另外，牙源性干细胞还可以通过诱导分化成神经系干细胞用于面神经损伤的修复，有研究指出这种诱导分化后的神经系干细胞在周围神经修复中拥有更好的效果[34]。Zhang等[35]将牙龈间充质干细胞通过一种非遗传方法诱导成神经嵴类干细胞，用诱导后的神经嵴类干细胞与神经导管组合移植修复大鼠面神经损伤，证实了牙龈间充质干细胞衍生的神经嵴类干细胞可以促进面神经再生，有可能成为组织工程的种子细胞，替代自体神经移植改善周围神经的再生。在Zhang等[36]的另一项研究中，运用3D生物打印技术将牙龈间充质干细胞球制成导管状的神经构建体[10]，见图4，利用这种神经构建体移植修复大鼠面神经颊支的节段性缺损，移植后第7周神经构建体移植组大鼠的行为学评分高于硅胶管对照组，移植后12周神经构建体移植组肌肉动作电位与自体神经移植组类似，该研究证实运用3D生物打印技术制成的牙龈间充质干细胞神经构建体具有促进大鼠面神经损伤再生的效果。Pereira等[37]用人体脱落乳牙干细胞联合聚乙醇酸管并结合自体神经移植修复大鼠面神经下颌支损伤模型，通过电生理和组织学评估移植效果，发现人体脱落乳牙干细胞可以促进面神经的再生，还能在体内分化为许旺细胞。"

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