TGF-β_3与牙髓干细胞在动物面神经损伤修复中的应用研究
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摘要
目的：
面神经的损伤在临床上较为常见，且损伤后很少能达到完美的功能恢复，严重影响患者及家属的心身健康及生活质量。随着干细胞研究的深入，利用骨髓干细胞对脊髓和颅脑损伤的治疗频频见于文献报道，但利用干细胞进行外周神经损伤的治疗报道较少。本研究旨在通过动物实验和分子生物学技术观察DPSCs与TGF-β_3联合干预对于面神经损伤的修复效果，并探讨其作用机制，为治疗面神经损伤提供新的方法。
方法：
（1）从新西兰幼兔前牙及磨牙牙髓组织中分离DPSCs进行体外培养，测定细胞克隆形成率、生长曲线、细胞爬片行HE染色、抗Vimentin、抗osteonectin、抗DSP、抗CD44免疫组化染色，鉴定DPSCs的增殖能力和多分化潜能的生物学特征。
（2）12只普通级瞬目反射正常的成年健康新西兰大白兔，面部两侧自身对照，随机分为自身正常对照组和上颊支缺损模型组，各组l2侧。于建模后7d、14d分别行光镜、电镜组织病理学检测，结合动物行为学观察、神经电生理检测技术对面神经上颊支缺损模型进行评价。
（3）成年健康新西兰大白兔48只（共96侧面神经），随机抽取24只（共48侧面神经）右侧设为TGF-β_3+DPSCs实验组（共24侧面神经），左侧设为TGF-β_3对照组1组（共24侧面神经），另外24只新西兰大白兔（共48侧面神经）右侧设为正常对照组（共24侧面神经），左侧设为PBS对照组2（共24侧面神经），分别制作面神经上颊支7mm缺损、损伤局部硅胶管套接的动物模型。于术后1周、1月、3月分别行大体形态、光镜、电镜组织学观察、神经电生理检测、GFAP和S100免疫组织化学染色等检测。
结果：
第一部分：1）原代培养的幼兔牙髓细胞多呈成纤维细胞样细胞，少数纺锤形或多角形，光镜下传代培养的细胞形态特点与原代培养无明显差异；从第1代到第3胞活率细胞数比分别为：94.7%、95.8%、95.2%；牙髓干细胞在低密度接种后能够形成克隆，幼兔牙髓细胞克隆集落形成率为10-21个/103细胞；2）幼兔牙髓细胞体外多次传代仍具有良好的增殖能力，24孔板计数法表明兔牙髓细胞潜伏期短，随后进入对数增长期，选取的第三代细胞均在五天达到对数生长期，约在第8天细胞达到平台期；细胞周期的测定结果为：G1期DNA含量占80.4%；G2期DNA含量占15.3%；S期DNA含量占4.3%；3）原代和次代克隆，免疫细胞化学对未经诱导的细胞进行表面标志物Vimentin、CD44、osteonectin、dsp鉴定，结果均为染色阳性。
第二部分：1）12只实验动物建模过程均较顺利，术中面神经暴露良好，操作可重复性佳。切口均获得I期愈合，动物在研究期间未发生切口感染及并发症，无实验兔死亡，动物存活率100%，建模成功率达100%；2）建模后所有实验动物术侧均出现面神经麻痹症状，2周时术侧面部轻度萎缩，兔唇明显偏向健侧；术后2周面部胡须运动功能评分，术侧分值为0.25±0.05，与健侧分值4分比较，差异有统计学意义（t=-249.16，P＜0.05）；3）面神经电生理检测结果显示，建模后1周、2周时，实验兔健侧组正常面神经潜伏期为（1.47±0.42）ms，神经动作电位最大波幅为（11.32±5.36）mV；刺激术侧组面神经中枢侧断端，不能引起同侧上唇方肌收缩；实验兔术侧面神经动作电位均未能引出；4）健侧组面神经HE染色可见，正常面神经上颊支纤维呈长条形，排列整齐，髓鞘密集，无退变，神经外膜连续；手术组面神经断端可见神经纤维连续性中断，断端部分脱髓鞘改变，神经外膜松散，神经纤维肿胀，板状层结构疏松，轴突呈空泡状；5）电镜观察显示，正常面神经轴突排列整齐，均匀一致，髓鞘结构完整、厚度较均匀、呈致密板层排列，胞核清晰；术后1周模型组神经鞘膜解离，板状结构变得模糊以致消失形成椭圆形小体，出现神经纤维球，轴浆内呈低电子密度；术后2周模型组轴突明显肿胀，其内微管、微丝数目明显减少，线粒体肿胀呈空泡样，电子密度降低；神经纤维排列紊乱，神经外膜连续性中断板层脱离。
第三部分：1）术后3月大体形态观察发现，与对照组1、2比较，实验组再生神经直径与近、远端神经干相当，无神经瘤形成，外膜血管丰富，质地坚韧；2）HE染色，术后3月实验组神经纤维排列较整齐，胞核浓密，束间血管多；对照组1神经纤维萎缩，再生神经纤维较少，扭曲较明显，呈盘旋状；对照组2部分轴突消失，神经纤维排列紊乱、髓鞘厚薄不均；3）电镜结果显示实验组的再生纤维以有髓神经纤维为主，形态规则，髓鞘板层结构清晰，轴浆内细胞器丰富；对照组1再生纤维髓鞘发育稍差，有髓神经纤维形态较规则，轴浆内细胞器较丰富；对照组2再生纤维髓鞘发育不良，板层结构紊乱，有髓神经纤维形态不规则，可见到变性的神经纤维；4）图像分析显示，实验组再生神经纤维总数多于其他两个对照组，差异有统计学意义（P＜0.05）；实验组再生神经纤维直径远远大于其他两个对照组，差异有统计学意义（P＜0.05）；实验组再生神经髓鞘厚度远远大于其他两个对照组，差异有统计学意义（P＜0.05）；5）神经电生理检测显示，实验组神经肌肉动作电位的潜伏期明显短于其他两个对照组[实验组（1.96±0.32）ms，对照组1（2.35±0.41）ms，对照组2（3.42±0.55）ms，P＜0.05]，而实验组神经肌肉动作电位的波幅明显高于其他两个对照组[实验组（11.06±3.25）mv，对照组1（8.40±1.68）mv，对照组2（4.62±0.77）mv，P＜005]；6）免疫组化结果显示，各处理组面神经核中均出现GFAP阳性细胞，且术后7天GFAP阳性细胞数TGF-β_3+DPSCs实验组＞TGF-β_3对照组1＞PBS对照组2（P＜0.05）；各处理组面神经中均出现S100阳性细胞，且S100阳性细胞数TGF-β_3+DPSCs实验组＞TGF-β_3对照组1＞PBS对照组2（P＜0.05）。
结论：
（1）本研究所培养的DPSCs增殖能力强，具有稳定的生物活性，可适应长期大量培养的需要。
（2）在传代第一代、第二代及第三代形成的克隆细胞率最高，可以选择前三代形成的克隆球进行细胞移植治疗。
（3）本研究建立的兔面神经上颊支缺损动物模型，制作简便、性质稳定、可重复性好、术后动物存活率和模型成功率高，且评价方法系统、可靠。
（4）DPSCs可以作为种子细胞应用于外周神经组织工程。
（5）TGF-β_3与牙髓干细胞联合应用能显著提高面神经损伤后修复的效果。
（6）用医用硅胶管、胶原蛋白海绵、DPSCs和TGF-β_3制备的人工神经符合神经组织学结构，对面神经缺损修复有效，为周围神经缺损的修复提供了一种新方法。
Objective
Facial nerve injury is common clinically, and the function can not be recoveredperfectly after facial nerve injury, which severely affected psychosomatic health andquality of life of patients and families. With the rapid development of the stem cellresearch, the reporter in the literature was more about using bone marrow stem cells forthe treatment of spinal cord and brain injury, but the method that to treatment peripheralnerve injuries using stem cells has not been reported. The purpose of this study was toinvestigate the effects of TGF-β_3and dental pulp stem cells in the regeneration of rabbitfacial nerve, to explore possible mechanism of action, and to provide a new method forthe treatment of facial nerve injury.
Methods:
(1) Dental pulp stem cells were separated and cultured in vitro from anterior teethand molar pulp tissue of New Zealand rabbit, and to test the cells clone forming rate, tomeasure cells growth curve by counting the number of cells, did HE staining andimmunhistochemistry staining of Vimentin, osteonectin、dsp and CD44. To identificationproliferation capacity and multiple differentiation potential of biological characteristics ofDPSCs.
(2)12New Zealand adult rabbits were selected randomly. These rabbits weredivided into two groups (the normal groups and the model groups).7days,14days afteroperation, a series of examinations were performed to evaluate the model, includinghistopathology testing, animal behavior observation, neuroelectrophysiological methods.
(3)48New Zealand adult rabbits（a total of96facial nerves）were randomly dividedinto4groups，respectively in treatment group (silicone guidance channel with collagenprolein sponge was filled with TGF-β_3+DPSCs), control group1(silicone guidancechannel with collagen prolein sponge was filled with TGF-β_3)，PBS control group2 (silicone guidance channel with collagen protein sponge was filled with PBS) and thenormal group．A7mm nerve defect was set up in the buccal branch of facial nerve andwas bridged with three sorts of artificial nerves. One week, one month, three months afteroperation， a series of examinations were performed respectively, including grossmorphology, histopathology testing, neuroelectrophysiological examination, GFAP andS100immunohistochemical stain.
Results:
Part one:1) Primary cultured rabbit dental pulp cells were fibroblast-like cells, afusiform or polygonal. characteristics were no difference between subcultured cell andprimary culture under a light microscope. The morphology character of the cells insubcultllring was as same as that in primary culture. Cell survival rate in the cell numbersfrom the first generation to the third generation were:94.7%,95.8%,95.2%. DPSCscould form clone after low density seeding.The cells clone forming rate was10-21/103cells.2) DPSCs have a perfect growing ability after multiple subculture.24holeplate counting method that rabbit dental pulp cells incubation period was short, thenentered the logarithmic growth phase, the third generation cell in five days to reach thelogarithmic growth phase, in about eighth days the cells reach the platform period. Theresult of the cell cycle: G1DNA content of80.4%G2; the content of DNA15.3%; S DNAcontent accounted for:4.3%.3) Immunhistochemistry staining showed that Vimentin、CD44、osteonectin and dsp of dental stem cells were positive in Clone of the original andpassaged.
Part two:1) All experiments were accomplished successfully, operation process wassmooth, animal survival rate was100%, and the success rate of modeling was100%.2)After modeling, all experimental animals appeared facial nerve paralysis symptoms in theoperation side. At2weeks after operation, the face on the operative side become mildatrophy. Facial whiskers motor function score showed that the scores of operative sidewere0.25±0.05, while the normal side scores were4points, there was a significantdifference (t=-249.16, P＜0.05).3) The neuroelectrophysiological examinations revealedthat the latency of nerve and muscle action conduction in the normal control groups were(1.47±0.42) ms, the wave amplitude of nerve and muscle action conduction in thenormal control groups were (11.32+5.36) mV. At one week、two weeks after operation,lateral nerve action potentials were unable to lead.4) Facial nerve HE staining showednormal facial nerve fibers elongated strip, arranged in neat rows, the myelin-intensive, no degeneration, the epineurium continuous; While surgery group facial nerve fiberdiscontinuity, ends part of the demyelination and the outer membrane was loose, the nervefiber was swollen, plate layer structure was loose, axonal vacuolization.5) Electronmicroscopy results showed that the normal facial nerve axons arranged in neat rows,cross-section showing circular, structural integrity of the myelin sheath, uniform thickness,dense lamellar arrangement, clear nucleus, clear Ranvier's node; At one week afteroperation, model group showed that the facial nerve sheath dissociation, platy structureblurred to disappear resulting in the formation of oval-shaped body, appeared nerve fiberballs，low electron density in the axoplasm; At two weeks after operation, the modelgroup results showed that the axon swelling obviously, the number of microtubules andactin filaments significantly reduced, mitochondria were vacuolated, lower electrondensity in myelin sheath， disordered arrangement of nerve fibers, epineuriumdiscontinuity and lamellar detachment.
Part three:1) At three months after operation, gross morphological observationfound that the diameter was almost the same between the regenerating nerve and near、distal nerve stem in the experimental group， no neuroma formation, adventitialangiogenesis was rich, tough texture.2) At three months after operation, HE stainingshowed that in the experimental group, the facial nerve membrane integrity, nerve fibersarranged in neat rows, dense nuclei. But in the control group1, the nerve fibers atrophy,regeneration fewer nerve fibers and distort obviously，was convoluted; in the controlgroup2, some axons disappeared, the nerve fibers arranged in disorder, the myelin sheathof uneven thickness.3) Electron microscopy results showed that the regenerated fibers inthe experimental group were mainly myelinated never fiber. The layer structure of myelinsheath was clear, and there were rich organells axoplasma. But in the control group1，themyelin dysplasia，disorder of the lamellar structure，myelinated nerve fibers with irregularshape, the degeneration of nerve fibers.4) Image analysis results showed that the totalnumber of regeneration of nerve fibers in the experimental group were more than theother control groups, statistical analysis was significant (P＜0.05). Diameter ofregenerating nerve fibers in the experimental group were greater than the other controlgroup, statistical analysis was significant (P＜0.05).5) At three months after operation,the neuroelectrophysiological examinations revealed that the latency of nerve and muscleaction conduction in the treatment group was shorter than the other control groups[thetreatment group:(1.96±0.32) ms, the control group1(2.35±0.41) ms, the control group2(3.42±0.55) ms], but the wave amplitude of nerve and muscle action conduction in the treatment group was obviously higher than that in the control group[the treatment group:(11.06±3.25) mv, the control group1(8.40±1.68) mv, the control group2(4.62±0.77)mv, P＜0.05].6) Facial nerve nuclear all appeared GFAP positive cells in each group,and the number of GFAP positive cells：TGF-of β_3+DPSCs experimental group>TGF-of β_3control group1> PBS control group2(P＜0.05); Facial nerves all appearedS100positive cells in each group，and the number of S100positive cells：TGF-β_3+DPSCs experimental group> TGF-β_3the control group1> PBS control group2(P<0.05).
Conclusion:
(1) DPSCs cultured in our experiment have both strong self-proliferation potentialand stable vital activity. Thus these cells are considered to be suitable for long-termculture in a large amount.
(2) The cell clone rate of DPSCs in the first、second and third generation is highest.These clone cells can be used as the source of grafting.
(3) Animal model established in this study is simple, stable, good repeatability,postoperative animal survival rate and modeling success rate is high. And these evaluationmethods are systematic, reliable.
(4) DPSCs can be applied as seed cells for peripheral nerve tissue engineering.
(5) The comination of TGF-β_3and DPSCs can improve the effects on the repair offacial nerve injury.
(6) The artificial nerve made of chitosan guidance channel, collagen protein sponge,DPSCs and nerve growth factor is the most effective in repairing nerve defect and for itaccorded with the histological structure of nerve. Therefore it may provide a new methodfor repairing the pepripheral nerve defect in clinic.
面神经的损伤在临床上较为常见，且损伤后很少能达到完美的功能恢复，严重影响患者及家属的心身健康及生活质量。随着干细胞研究的深入，利用骨髓干细胞对脊髓和颅脑损伤的治疗频频见于文献报道，但利用干细胞进行外周神经损伤的治疗报道较少。本研究旨在通过动物实验和分子生物学技术观察DPSCs与TGF-β_3联合干预对于面神经损伤的修复效果，并探讨其作用机制，为治疗面神经损伤提供新的方法。
方法：
（1）从新西兰幼兔前牙及磨牙牙髓组织中分离DPSCs进行体外培养，测定细胞克隆形成率、生长曲线、细胞爬片行HE染色、抗Vimentin、抗osteonectin、抗DSP、抗CD44免疫组化染色，鉴定DPSCs的增殖能力和多分化潜能的生物学特征。
（2）12只普通级瞬目反射正常的成年健康新西兰大白兔，面部两侧自身对照，随机分为自身正常对照组和上颊支缺损模型组，各组l2侧。于建模后7d、14d分别行光镜、电镜组织病理学检测，结合动物行为学观察、神经电生理检测技术对面神经上颊支缺损模型进行评价。
（3）成年健康新西兰大白兔48只（共96侧面神经），随机抽取24只（共48侧面神经）右侧设为TGF-β_3+DPSCs实验组（共24侧面神经），左侧设为TGF-β_3对照组1组（共24侧面神经），另外24只新西兰大白兔（共48侧面神经）右侧设为正常对照组（共24侧面神经），左侧设为PBS对照组2（共24侧面神经），分别制作面神经上颊支7mm缺损、损伤局部硅胶管套接的动物模型。于术后1周、1月、3月分别行大体形态、光镜、电镜组织学观察、神经电生理检测、GFAP和S100免疫组织化学染色等检测。
结果：
第一部分：1）原代培养的幼兔牙髓细胞多呈成纤维细胞样细胞，少数纺锤形或多角形，光镜下传代培养的细胞形态特点与原代培养无明显差异；从第1代到第3胞活率细胞数比分别为：94.7%、95.8%、95.2%；牙髓干细胞在低密度接种后能够形成克隆，幼兔牙髓细胞克隆集落形成率为10-21个/103细胞；2）幼兔牙髓细胞体外多次传代仍具有良好的增殖能力，24孔板计数法表明兔牙髓细胞潜伏期短，随后进入对数增长期，选取的第三代细胞均在五天达到对数生长期，约在第8天细胞达到平台期；细胞周期的测定结果为：G1期DNA含量占80.4%；G2期DNA含量占15.3%；S期DNA含量占4.3%；3）原代和次代克隆，免疫细胞化学对未经诱导的细胞进行表面标志物Vimentin、CD44、osteonectin、dsp鉴定，结果均为染色阳性。
第二部分：1）12只实验动物建模过程均较顺利，术中面神经暴露良好，操作可重复性佳。切口均获得I期愈合，动物在研究期间未发生切口感染及并发症，无实验兔死亡，动物存活率100%，建模成功率达100%；2）建模后所有实验动物术侧均出现面神经麻痹症状，2周时术侧面部轻度萎缩，兔唇明显偏向健侧；术后2周面部胡须运动功能评分，术侧分值为0.25±0.05，与健侧分值4分比较，差异有统计学意义（t=-249.16，P＜0.05）；3）面神经电生理检测结果显示，建模后1周、2周时，实验兔健侧组正常面神经潜伏期为（1.47±0.42）ms，神经动作电位最大波幅为（11.32±5.36）mV；刺激术侧组面神经中枢侧断端，不能引起同侧上唇方肌收缩；实验兔术侧面神经动作电位均未能引出；4）健侧组面神经HE染色可见，正常面神经上颊支纤维呈长条形，排列整齐，髓鞘密集，无退变，神经外膜连续；手术组面神经断端可见神经纤维连续性中断，断端部分脱髓鞘改变，神经外膜松散，神经纤维肿胀，板状层结构疏松，轴突呈空泡状；5）电镜观察显示，正常面神经轴突排列整齐，均匀一致，髓鞘结构完整、厚度较均匀、呈致密板层排列，胞核清晰；术后1周模型组神经鞘膜解离，板状结构变得模糊以致消失形成椭圆形小体，出现神经纤维球，轴浆内呈低电子密度；术后2周模型组轴突明显肿胀，其内微管、微丝数目明显减少，线粒体肿胀呈空泡样，电子密度降低；神经纤维排列紊乱，神经外膜连续性中断板层脱离。
第三部分：1）术后3月大体形态观察发现，与对照组1、2比较，实验组再生神经直径与近、远端神经干相当，无神经瘤形成，外膜血管丰富，质地坚韧；2）HE染色，术后3月实验组神经纤维排列较整齐，胞核浓密，束间血管多；对照组1神经纤维萎缩，再生神经纤维较少，扭曲较明显，呈盘旋状；对照组2部分轴突消失，神经纤维排列紊乱、髓鞘厚薄不均；3）电镜结果显示实验组的再生纤维以有髓神经纤维为主，形态规则，髓鞘板层结构清晰，轴浆内细胞器丰富；对照组1再生纤维髓鞘发育稍差，有髓神经纤维形态较规则，轴浆内细胞器较丰富；对照组2再生纤维髓鞘发育不良，板层结构紊乱，有髓神经纤维形态不规则，可见到变性的神经纤维；4）图像分析显示，实验组再生神经纤维总数多于其他两个对照组，差异有统计学意义（P＜0.05）；实验组再生神经纤维直径远远大于其他两个对照组，差异有统计学意义（P＜0.05）；实验组再生神经髓鞘厚度远远大于其他两个对照组，差异有统计学意义（P＜0.05）；5）神经电生理检测显示，实验组神经肌肉动作电位的潜伏期明显短于其他两个对照组[实验组（1.96±0.32）ms，对照组1（2.35±0.41）ms，对照组2（3.42±0.55）ms，P＜0.05]，而实验组神经肌肉动作电位的波幅明显高于其他两个对照组[实验组（11.06±3.25）mv，对照组1（8.40±1.68）mv，对照组2（4.62±0.77）mv，P＜005]；6）免疫组化结果显示，各处理组面神经核中均出现GFAP阳性细胞，且术后7天GFAP阳性细胞数TGF-β_3+DPSCs实验组＞TGF-β_3对照组1＞PBS对照组2（P＜0.05）；各处理组面神经中均出现S100阳性细胞，且S100阳性细胞数TGF-β_3+DPSCs实验组＞TGF-β_3对照组1＞PBS对照组2（P＜0.05）。
结论：
（1）本研究所培养的DPSCs增殖能力强，具有稳定的生物活性，可适应长期大量培养的需要。
（2）在传代第一代、第二代及第三代形成的克隆细胞率最高，可以选择前三代形成的克隆球进行细胞移植治疗。
（3）本研究建立的兔面神经上颊支缺损动物模型，制作简便、性质稳定、可重复性好、术后动物存活率和模型成功率高，且评价方法系统、可靠。
（4）DPSCs可以作为种子细胞应用于外周神经组织工程。
（5）TGF-β_3与牙髓干细胞联合应用能显著提高面神经损伤后修复的效果。
（6）用医用硅胶管、胶原蛋白海绵、DPSCs和TGF-β_3制备的人工神经符合神经组织学结构，对面神经缺损修复有效，为周围神经缺损的修复提供了一种新方法。
Objective
Facial nerve injury is common clinically, and the function can not be recoveredperfectly after facial nerve injury, which severely affected psychosomatic health andquality of life of patients and families. With the rapid development of the stem cellresearch, the reporter in the literature was more about using bone marrow stem cells forthe treatment of spinal cord and brain injury, but the method that to treatment peripheralnerve injuries using stem cells has not been reported. The purpose of this study was toinvestigate the effects of TGF-β_3and dental pulp stem cells in the regeneration of rabbitfacial nerve, to explore possible mechanism of action, and to provide a new method forthe treatment of facial nerve injury.
Methods:
(1) Dental pulp stem cells were separated and cultured in vitro from anterior teethand molar pulp tissue of New Zealand rabbit, and to test the cells clone forming rate, tomeasure cells growth curve by counting the number of cells, did HE staining andimmunhistochemistry staining of Vimentin, osteonectin、dsp and CD44. To identificationproliferation capacity and multiple differentiation potential of biological characteristics ofDPSCs.
(2)12New Zealand adult rabbits were selected randomly. These rabbits weredivided into two groups (the normal groups and the model groups).7days,14days afteroperation, a series of examinations were performed to evaluate the model, includinghistopathology testing, animal behavior observation, neuroelectrophysiological methods.
(3)48New Zealand adult rabbits（a total of96facial nerves）were randomly dividedinto4groups，respectively in treatment group (silicone guidance channel with collagenprolein sponge was filled with TGF-β_3+DPSCs), control group1(silicone guidancechannel with collagen prolein sponge was filled with TGF-β_3)，PBS control group2 (silicone guidance channel with collagen protein sponge was filled with PBS) and thenormal group．A7mm nerve defect was set up in the buccal branch of facial nerve andwas bridged with three sorts of artificial nerves. One week, one month, three months afteroperation， a series of examinations were performed respectively, including grossmorphology, histopathology testing, neuroelectrophysiological examination, GFAP andS100immunohistochemical stain.
Results:
Part one:1) Primary cultured rabbit dental pulp cells were fibroblast-like cells, afusiform or polygonal. characteristics were no difference between subcultured cell andprimary culture under a light microscope. The morphology character of the cells insubcultllring was as same as that in primary culture. Cell survival rate in the cell numbersfrom the first generation to the third generation were:94.7%,95.8%,95.2%. DPSCscould form clone after low density seeding.The cells clone forming rate was10-21/103cells.2) DPSCs have a perfect growing ability after multiple subculture.24holeplate counting method that rabbit dental pulp cells incubation period was short, thenentered the logarithmic growth phase, the third generation cell in five days to reach thelogarithmic growth phase, in about eighth days the cells reach the platform period. Theresult of the cell cycle: G1DNA content of80.4%G2; the content of DNA15.3%; S DNAcontent accounted for:4.3%.3) Immunhistochemistry staining showed that Vimentin、CD44、osteonectin and dsp of dental stem cells were positive in Clone of the original andpassaged.
Part two:1) All experiments were accomplished successfully, operation process wassmooth, animal survival rate was100%, and the success rate of modeling was100%.2)After modeling, all experimental animals appeared facial nerve paralysis symptoms in theoperation side. At2weeks after operation, the face on the operative side become mildatrophy. Facial whiskers motor function score showed that the scores of operative sidewere0.25±0.05, while the normal side scores were4points, there was a significantdifference (t=-249.16, P＜0.05).3) The neuroelectrophysiological examinations revealedthat the latency of nerve and muscle action conduction in the normal control groups were(1.47±0.42) ms, the wave amplitude of nerve and muscle action conduction in thenormal control groups were (11.32+5.36) mV. At one week、two weeks after operation,lateral nerve action potentials were unable to lead.4) Facial nerve HE staining showednormal facial nerve fibers elongated strip, arranged in neat rows, the myelin-intensive, no degeneration, the epineurium continuous; While surgery group facial nerve fiberdiscontinuity, ends part of the demyelination and the outer membrane was loose, the nervefiber was swollen, plate layer structure was loose, axonal vacuolization.5) Electronmicroscopy results showed that the normal facial nerve axons arranged in neat rows,cross-section showing circular, structural integrity of the myelin sheath, uniform thickness,dense lamellar arrangement, clear nucleus, clear Ranvier's node; At one week afteroperation, model group showed that the facial nerve sheath dissociation, platy structureblurred to disappear resulting in the formation of oval-shaped body, appeared nerve fiberballs，low electron density in the axoplasm; At two weeks after operation, the modelgroup results showed that the axon swelling obviously, the number of microtubules andactin filaments significantly reduced, mitochondria were vacuolated, lower electrondensity in myelin sheath， disordered arrangement of nerve fibers, epineuriumdiscontinuity and lamellar detachment.
Part three:1) At three months after operation, gross morphological observationfound that the diameter was almost the same between the regenerating nerve and near、distal nerve stem in the experimental group， no neuroma formation, adventitialangiogenesis was rich, tough texture.2) At three months after operation, HE stainingshowed that in the experimental group, the facial nerve membrane integrity, nerve fibersarranged in neat rows, dense nuclei. But in the control group1, the nerve fibers atrophy,regeneration fewer nerve fibers and distort obviously，was convoluted; in the controlgroup2, some axons disappeared, the nerve fibers arranged in disorder, the myelin sheathof uneven thickness.3) Electron microscopy results showed that the regenerated fibers inthe experimental group were mainly myelinated never fiber. The layer structure of myelinsheath was clear, and there were rich organells axoplasma. But in the control group1，themyelin dysplasia，disorder of the lamellar structure，myelinated nerve fibers with irregularshape, the degeneration of nerve fibers.4) Image analysis results showed that the totalnumber of regeneration of nerve fibers in the experimental group were more than theother control groups, statistical analysis was significant (P＜0.05). Diameter ofregenerating nerve fibers in the experimental group were greater than the other controlgroup, statistical analysis was significant (P＜0.05).5) At three months after operation,the neuroelectrophysiological examinations revealed that the latency of nerve and muscleaction conduction in the treatment group was shorter than the other control groups[thetreatment group:(1.96±0.32) ms, the control group1(2.35±0.41) ms, the control group2(3.42±0.55) ms], but the wave amplitude of nerve and muscle action conduction in the treatment group was obviously higher than that in the control group[the treatment group:(11.06±3.25) mv, the control group1(8.40±1.68) mv, the control group2(4.62±0.77)mv, P＜0.05].6) Facial nerve nuclear all appeared GFAP positive cells in each group,and the number of GFAP positive cells：TGF-of β_3+DPSCs experimental group>TGF-of β_3control group1> PBS control group2(P＜0.05); Facial nerves all appearedS100positive cells in each group，and the number of S100positive cells：TGF-β_3+DPSCs experimental group> TGF-β_3the control group1> PBS control group2(P<0.05).
Conclusion:
(1) DPSCs cultured in our experiment have both strong self-proliferation potentialand stable vital activity. Thus these cells are considered to be suitable for long-termculture in a large amount.
(2) The cell clone rate of DPSCs in the first、second and third generation is highest.These clone cells can be used as the source of grafting.
(3) Animal model established in this study is simple, stable, good repeatability,postoperative animal survival rate and modeling success rate is high. And these evaluationmethods are systematic, reliable.
(4) DPSCs can be applied as seed cells for peripheral nerve tissue engineering.
(5) The comination of TGF-β_3and DPSCs can improve the effects on the repair offacial nerve injury.
(6) The artificial nerve made of chitosan guidance channel, collagen protein sponge,DPSCs and nerve growth factor is the most effective in repairing nerve defect and for itaccorded with the histological structure of nerve. Therefore it may provide a new methodfor repairing the pepripheral nerve defect in clinic.
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