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Article(id=1194617492925550898, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1194617490446721194, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.1084.2024.1118, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1692028800000, receivedDateStr=2023-08-15, revisedDate=null, revisedDateStr=null, acceptedDate=1697040000000, acceptedDateStr=2023-10-12, onlineDate=1762748605232, onlineDateStr=2025-11-10, pubDate=1740672000000, pubDateStr=2025-02-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762748605232, onlineIssueDateStr=2025-11-10, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762748605232, creator=13701087609, updateTime=1762748605232, updator=13701087609, issue=Issue{id=1194617490446721194, tenantId=1146029695717560320, journalId=1189873630562394117, year='2025', volume='50', issue='2', pageStart='123', pageEnd='244', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1762748604641, creator=13701087609, updateTime=1762749162199, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1194619829073191185, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1194617490446721194, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1194619829073191186, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1194617490446721194, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=207, endPage=213, ext={EN=ArticleExt(id=1194617493147849012, articleId=1194617492925550898, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Comparison of neuroprotective effects of hUC-MSCs-Exos on hypoxic-ischemic brain injury in neonatal mice by different administration modes, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the comparative neuroprotective effects of human umbilical cord mesenchymal stem cells (hUC-MSCs-Exos) administered via different routes on hypoxic ischemic brain damage (HIBD) in neonatal mice. Methods Healthy one-week-old SPF-grade BALB/c mice were randomly divided into 4 groups: sham operation group (n=6), model group (n=6), exosome group 1 (n=8), exosome group 2 (n=8). HIBD was induced using the Rice-Vannucci method. Exosome group 1 and Exosome group 2 were intraperitoneal injection/intranasal drip of phosphate buffer (PBS) 100 μl containing 10 μl exosomes within 24 h after successful modeling, respectively. Sham operation and model groups were intraperitoneal injection of PBS 100 μl. On the 7th day after the intervention, neuromotor function was assessed using the horizontal grid test and pole climbing test. On the 2nd day after the evaluation, all mice were killed and their brains were removed by decapitation. HE staining was used to observe the pathological injury of brain tissue, toluidine blue staining was used to observe the survival of neurons in cerebral cortex, and TUNEL staining was used to observe the apoptosis of cerebral cortex cells. Results Compared with sham operation group, model group, exosome group 1 and exosome group 2 exhibited increased hind limb drops in horizontal grid test and climbing scores (P<0.05). No significant difference was found in model group, exosome group 1 and exosome group 2 in these measures (P<0.05). Significant pathology was observed in model group, exosome group 1 and exosome group 2 compared to sham operation group (P<0.05), with significantly reduced damage in exosome group 1 and exosome group 2 compared to model group (P<0.05). Compared with sham operation group, Nissl body count was lower in model group and exosome group 1 and exosome group 2, with a higher count in exosome group 2 compared to exosome group 1 (P<0.05). Compared with sham operation group, apoptotic cells were higher in model group and exosome group 1 and exosome group 2, with a significant reduction in exosome group 1 and exosome group 2 compared to model group, and the lowest in exosome group 2 (P<0.05). Conclusions hUC-MSCs-Exos can improve the neuronal motor function, promote neuron repair and inhibit apoptosis in HIBD mice. Intranasal administration of hUC-MSCs-Exos is more effective than intraperitoneal administration for reducing neuronal apoptosis in HIBP neonatal mice, offering a convenient and rapid method suitable for clinical application.

, correspAuthors=Yi-Pa Sai, authorNote=null, correspAuthorsNote=
E-mail:
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目的 比较人脐血间充质干细胞来源的外泌体(hUC-MSCs-Exos)经不同给药方式对缺氧缺血性脑损伤(HIBD)小鼠神经行为学的影响及脑组织损伤修复的效果，探索更方便、更高效的给药途径。方法 健康1周龄SPF级BALB/c小鼠随机分为4组：假手术组(n=6)、模型组(n=6)、外泌体1组(n=8)、外泌体2组(n=8)。采用Rice-Vannucci法制备HIBD小鼠模型。外泌体1组、外泌体2组小鼠分别于造模成功后24 h内经腹腔注射或经鼻腔滴入含有10 μl外泌体的PBS 100 μl，假手术组及模型组经腹腔注射PBS 100 μl。干预后7 d，采用水平网格测试和爬杆实验评估各组小鼠的神经运动功能，在评估完成后第2天处死所有小鼠，断头取脑，HE染色观察小鼠脑组织的病理损伤情况，甲苯胺蓝染色观察小鼠脑组织皮质区神经元的存活情况，TUNEL染色观察小鼠脑组织皮质区细胞的凋亡情况。结果 与假手术组比较，模型组、外泌体1组、外泌体2组小鼠水平网格测试中后肢掉落次数明显增多，爬杆实验评分明显增高(P<0.05)，而模型组、外泌体1组、外泌体2组小鼠水平网格测试中后肢掉落次数及爬杆实验评分比较差异均无统计学意义(P>0.05)。与假手术组比较，模型组、外泌体1组、外泌体2组小鼠脑组织均出现了明显的病理损伤，皮质区尼氏小体计数明显减少、细胞凋亡率明显增高(P<0.05)；与模型组比较，外泌体1组、外泌体2组小鼠的脑组织病理损伤明显减轻，皮质区尼氏小体计数明显增多、细胞凋亡率明显降低(P<0.05)；与外泌体1组比较，外泌体2组小鼠的脑组织病理损伤程度差异无统计学意义(P>0.05)，但皮质区尼氏小体计数明显增多、细胞凋亡率明显降低(P<0.05)。结论 hUC-MSCs-Exos可一定程度改善HIBD小鼠的神经运动功能，促进神经元修复，抑制细胞凋亡；经鼻腔给予hUC-MSCs-Exos在减少HIBD新生小鼠神经细胞凋亡方面的作用较经腹腔给药明显，且给药方便快捷，利于临床推广应用。

, correspAuthors=赛依帕, authorNote=null, correspAuthorsNote=
赛依帕，E-mail：
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胡筱霞，硕士研究生，主治医师，主要从事新生儿缺氧缺血性脑病神经损伤与修复方面的研究

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胡筱霞，硕士研究生，主治医师，主要从事新生儿缺氧缺血性脑病神经损伤与修复方面的研究

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胡筱霞，硕士研究生，主治医师，主要从事新生儿缺氧缺血性脑病神经损伤与修复方面的研究

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Int J Mol Sci, 2016, 17(12): 2078., articleTitle=Oxidative stress in hypoxic-ischemic encephalopathy: molecular mechanisms and therapeutic strategies, refAbstract=null), Reference(id=1194646582126682415, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, doi=null, pmid=null, pmcid=null, year=2019, volume=35, issue=20, pageStart=3172, pageEnd=3175, url=null, language=null, rfNumber=[34], rfOrder=33, authorNames=吴静静, journalName=现代医药卫生, refType=null, unstructuredReference=吴静静. 新生儿缺氧缺血性脑病的发病机制及相关治疗进展[J]. 现代医药卫生, 2019, 35(20): 3172-3175., articleTitle=新生儿缺氧缺血性脑病的发病机制及相关治疗进展, refAbstract=null)], funds=[Fund(id=1194646578922234117, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=22JR5RA689, language=EN, fundingSource=Natural Science Foundation of Gansu Province(22JR5RA689), fundOrder=null, country=null), Fund(id=1194646579014508806, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=22JR5RA689, language=CN, fundingSource=甘肃省自然科学基金(22JR5RA689), fundOrder=null, country=null), Fund(id=1194646579098394887, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=22JR5RA701, language=EN, fundingSource=Gansu Youth Science and Technology Fund Project(22JR5RA701), fundOrder=null, country=null), Fund(id=1194646579165503752, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=22JR5RA701, language=CN, fundingSource=甘肃省青年科技基金计划项目(22JR5RA701), fundOrder=null, country=null), Fund(id=1194646579241001225, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=GSSZDSYS2020-10, language=EN, fundingSource=Key Laboratory of Molecular Diagnosis and Precision Therapy of Surgical Tumor of Gansu Province(GSSZDSYS2020-10), fundOrder=null, country=null), Fund(id=1194646579299721482, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=GSSZDSYS2020-10, language=CN, fundingSource=甘肃省外科肿瘤分子诊断与精准治疗重点实验室项目(GSSZDSYS2020-10), fundOrder=null, country=null), Fund(id=1194646579358441739, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=20GSSY1-13, language=EN, fundingSource=Research Foundation of People's Hospital of Gansu Province(20GSSY1-13), fundOrder=null, country=null), Fund(id=1194646579438133516, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, awardId=20GSSY1-13, language=CN, fundingSource=甘肃省人民医院院内科研基金(20GSSY1-13), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1194646575340298416, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, xref=null, ext=[AuthorCompanyExt(id=1194646575357075633, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, companyId=1194646575340298416, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Pediatrics, People's Hospital of Gansu Province/the First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou, Gansu 730030, China), AuthorCompanyExt(id=1194646575369658546, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, companyId=1194646575340298416, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=甘肃省人民医院/甘肃中医药大学第一临床医学院儿科，甘肃兰州 730030)])], figs=[ArticleFig(id=1194646578087567611, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, language=EN, label=Fig.1, caption=Verified result of hUC-MSCs-Exos, figureFileSmall=Dh/PU4HdSDvL4hgsbg2AvA==, figureFileBig=vEl4OEdHfQ5h3RZk6oM2EQ==, tableContent=null), ArticleFig(id=1194646578154676476, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, language=CN, label=图1, caption=hUC-MSCs-Exos的鉴定

hUC-MSCs-Exos. 人脐血间充质干细胞来源外泌体；A. 透射电子显微镜下观察hUC-MSCs-Exos形态；B. hUC-MSCs-Exos粒径分析(纳米粒子跟踪分析器)；C. Western blotting检测hUC-MSCs-Exos表面标记蛋白TSG101的表达

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hUC-MSCs-Exos. 人脐血间充质干细胞来源外泌体

, figureFileSmall=BAIk24e89YwBmKL3DsffbA==, figureFileBig=XSl5soaKbPCYvd3vzvlzPw==, tableContent=null), ArticleFig(id=1194646578431500543, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, language=EN, label=Fig.3, caption=Effect of hUC-MSCs-Exos on Nissl bodies in cerebral cortex of mouse brain tissues (toluidine blue staining ×400), figureFileSmall=uzJDXmjDfxfI0rCmxUGEvg==, figureFileBig=nTKWVUAVFh4UlIPIGew9lQ==, tableContent=null), ArticleFig(id=1194646578506998016, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, language=CN, label=图3, caption=hUC-MSCs-Exos对小鼠脑组织皮质区尼氏小体的影响(甲苯胺蓝染色 ×400)

hUC-MSCs-Exos. 人脐血间充质干细胞来源外泌体

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Comparison of neurobehavioral scores of mice in each group ($\bar{x}±s$)

, figureFileSmall=null, figureFileBig=null, tableContent=
组别

水平网格测试中后肢

掉落次数(次)

爬杆实验评分

(分)

假手术组(n=6)0.67±0.821.50±1.23
模型组(n=6)5.83±1.17(1)7.67±1.03(1)
外泌体1组(n=8)5.10±1.76(1)6.13±1.30(1)
外泌体2组(n=8)5.05±1.04(1)6.08±1.19(1)
F38.56329.987
P<0.001<0.001
), ArticleFig(id=1194646578653798658, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, language=CN, label=表1, caption=

各组小鼠神经行为学评估结果比较($\bar{x}±s$)

, figureFileSmall=null, figureFileBig=null, tableContent=
组别

水平网格测试中后肢

掉落次数(次)

爬杆实验评分

(分)

假手术组(n=6)0.67±0.821.50±1.23
模型组(n=6)5.83±1.17(1)7.67±1.03(1)
外泌体1组(n=8)5.10±1.76(1)6.13±1.30(1)
外泌体2组(n=8)5.05±1.04(1)6.08±1.19(1)
F38.56329.987
P<0.001<0.001
), ArticleFig(id=1194646578729296131, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, language=EN, label=Tab.2, caption=

Comparison of Nissl body count and percentage of apoptosis in cerebral cortex of mouse brain tissues in each group ($\bar{x}±s$)

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组别尼氏小体计数(个/400倍视野)细胞凋亡率(%)
假手术组(n=6)80.06±9.320.66±0.91
模型组(n=6)3.00±0.76(1)31.45±5.32(1)
外泌体1组(n=8)18.71±4.14(1)(2)15.34±4.03(1)(2)
外泌体2组(n=8)41.59±7.58(1)(2)(3)7.12±1.64(1)(2)(3)
F173.42094.287
P<0.001<0.001
), ArticleFig(id=1194646578800599300, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1194617492925550898, language=CN, label=表2, caption=

各组小鼠脑组织皮质区尼氏小体计数及细胞凋亡率比较($\bar{x}±s$)

, figureFileSmall=null, figureFileBig=null, tableContent=
组别尼氏小体计数(个/400倍视野)细胞凋亡率(%)
假手术组(n=6)80.06±9.320.66±0.91
模型组(n=6)3.00±0.76(1)31.45±5.32(1)
外泌体1组(n=8)18.71±4.14(1)(2)15.34±4.03(1)(2)
外泌体2组(n=8)41.59±7.58(1)(2)(3)7.12±1.64(1)(2)(3)
F173.42094.287
P<0.001<0.001
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hUC-MSCs-Exos不同给药方式对缺氧缺血性脑损伤新生小鼠的神经保护作用
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胡筱霞 , 赛依帕 * , 陈星星 , 崔维静 , 王三萍 , 罗璇 , 吴世丽
解放军医学杂志 | 基础研究 2025,50(2): 207-213
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解放军医学杂志 | 基础研究 2025, 50(2): 207-213
hUC-MSCs-Exos不同给药方式对缺氧缺血性脑损伤新生小鼠的神经保护作用
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胡筱霞, 赛依帕* , 陈星星, 崔维静, 王三萍, 罗璇, 吴世丽
作者信息
  • 甘肃省人民医院/甘肃中医药大学第一临床医学院儿科，甘肃兰州 730030

    • 胡筱霞，硕士研究生，主治医师，主要从事新生儿缺氧缺血性脑病神经损伤与修复方面的研究

通讯作者:

赛依帕，E-mail：
Comparison of neuroprotective effects of hUC-MSCs-Exos on hypoxic-ischemic brain injury in neonatal mice by different administration modes
Xiao-Xia Hu, Yi-Pa Sai* , Xing-Xing Chen, Wei-Jing Cui, San-Ping Wang, Xuan Luo, Shi-Li Wu
Affiliations
  • Department of Pediatrics, People's Hospital of Gansu Province/the First Clinical Medical College of Gansu University of Chinese Medicine, Lanzhou, Gansu 730030, China
出版时间: 2025-02-28 doi: 10.11855/j.issn.0577-7402.1084.2024.1118
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摘要
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目的 比较人脐血间充质干细胞来源的外泌体(hUC-MSCs-Exos)经不同给药方式对缺氧缺血性脑损伤(HIBD)小鼠神经行为学的影响及脑组织损伤修复的效果，探索更方便、更高效的给药途径。方法 健康1周龄SPF级BALB/c小鼠随机分为4组：假手术组(n=6)、模型组(n=6)、外泌体1组(n=8)、外泌体2组(n=8)。采用Rice-Vannucci法制备HIBD小鼠模型。外泌体1组、外泌体2组小鼠分别于造模成功后24 h内经腹腔注射或经鼻腔滴入含有10 μl外泌体的PBS 100 μl，假手术组及模型组经腹腔注射PBS 100 μl。干预后7 d，采用水平网格测试和爬杆实验评估各组小鼠的神经运动功能，在评估完成后第2天处死所有小鼠，断头取脑，HE染色观察小鼠脑组织的病理损伤情况，甲苯胺蓝染色观察小鼠脑组织皮质区神经元的存活情况，TUNEL染色观察小鼠脑组织皮质区细胞的凋亡情况。结果 与假手术组比较，模型组、外泌体1组、外泌体2组小鼠水平网格测试中后肢掉落次数明显增多，爬杆实验评分明显增高(P<0.05)，而模型组、外泌体1组、外泌体2组小鼠水平网格测试中后肢掉落次数及爬杆实验评分比较差异均无统计学意义(P>0.05)。与假手术组比较，模型组、外泌体1组、外泌体2组小鼠脑组织均出现了明显的病理损伤，皮质区尼氏小体计数明显减少、细胞凋亡率明显增高(P<0.05)；与模型组比较，外泌体1组、外泌体2组小鼠的脑组织病理损伤明显减轻，皮质区尼氏小体计数明显增多、细胞凋亡率明显降低(P<0.05)；与外泌体1组比较，外泌体2组小鼠的脑组织病理损伤程度差异无统计学意义(P>0.05)，但皮质区尼氏小体计数明显增多、细胞凋亡率明显降低(P<0.05)。结论 hUC-MSCs-Exos可一定程度改善HIBD小鼠的神经运动功能，促进神经元修复，抑制细胞凋亡；经鼻腔给予hUC-MSCs-Exos在减少HIBD新生小鼠神经细胞凋亡方面的作用较经腹腔给药明显，且给药方便快捷，利于临床推广应用。

缺氧缺血性脑损伤  /  人脐血间充质干细胞来源外泌体  /  神经保护  /  鼻内注射

Objective To investigate the comparative neuroprotective effects of human umbilical cord mesenchymal stem cells (hUC-MSCs-Exos) administered via different routes on hypoxic ischemic brain damage (HIBD) in neonatal mice. Methods Healthy one-week-old SPF-grade BALB/c mice were randomly divided into 4 groups: sham operation group (n=6), model group (n=6), exosome group 1 (n=8), exosome group 2 (n=8). HIBD was induced using the Rice-Vannucci method. Exosome group 1 and Exosome group 2 were intraperitoneal injection/intranasal drip of phosphate buffer (PBS) 100 μl containing 10 μl exosomes within 24 h after successful modeling, respectively. Sham operation and model groups were intraperitoneal injection of PBS 100 μl. On the 7th day after the intervention, neuromotor function was assessed using the horizontal grid test and pole climbing test. On the 2nd day after the evaluation, all mice were killed and their brains were removed by decapitation. HE staining was used to observe the pathological injury of brain tissue, toluidine blue staining was used to observe the survival of neurons in cerebral cortex, and TUNEL staining was used to observe the apoptosis of cerebral cortex cells. Results Compared with sham operation group, model group, exosome group 1 and exosome group 2 exhibited increased hind limb drops in horizontal grid test and climbing scores (P<0.05). No significant difference was found in model group, exosome group 1 and exosome group 2 in these measures (P<0.05). Significant pathology was observed in model group, exosome group 1 and exosome group 2 compared to sham operation group (P<0.05), with significantly reduced damage in exosome group 1 and exosome group 2 compared to model group (P<0.05). Compared with sham operation group, Nissl body count was lower in model group and exosome group 1 and exosome group 2, with a higher count in exosome group 2 compared to exosome group 1 (P<0.05). Compared with sham operation group, apoptotic cells were higher in model group and exosome group 1 and exosome group 2, with a significant reduction in exosome group 1 and exosome group 2 compared to model group, and the lowest in exosome group 2 (P<0.05). Conclusions hUC-MSCs-Exos can improve the neuronal motor function, promote neuron repair and inhibit apoptosis in HIBD mice. Intranasal administration of hUC-MSCs-Exos is more effective than intraperitoneal administration for reducing neuronal apoptosis in HIBP neonatal mice, offering a convenient and rapid method suitable for clinical application.

hypoxic ischemic brain damage  /  exosomes of human umbilical cord mesenchymal stem cells  /  neuroprotection  /  nasal injection
胡筱霞, 赛依帕, 陈星星, 崔维静, 王三萍, 罗璇, 吴世丽. hUC-MSCs-Exos不同给药方式对缺氧缺血性脑损伤新生小鼠的神经保护作用. 解放军医学杂志, 2025 , 50 (2) : 207 -213 . DOI: 10.11855/j.issn.0577-7402.1084.2024.1118
Xiao-Xia Hu, Yi-Pa Sai, Xing-Xing Chen, Wei-Jing Cui, San-Ping Wang, Xuan Luo, Shi-Li Wu. Comparison of neuroprotective effects of hUC-MSCs-Exos on hypoxic-ischemic brain injury in neonatal mice by different administration modes[J]. Medical Journal of Chinese People’s Liberation Army, 2025 , 50 (2) : 207 -213 . DOI: 10.11855/j.issn.0577-7402.1084.2024.1118
正文
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新生儿缺氧缺血性脑病(hypoxic-ischemic encephalopathy，HIE)是围生期窒息引起的部分或完全缺氧、脑血流减少或暂停所导致的一种不可逆的新生儿脑损伤[1]，也是一种导致高病死率及严重神经系统后遗症的新生儿期疾病。国内外流行病学调查显示，HIE的发病率存在明显的地域差异，发达国家及地区为1‰~3‰，发展中国家及地区可高达20‰，我国的发病率为3‰~6‰[2]。HIE是新生儿死亡的三大病因之一，占全球新生儿死亡人数的25%[3]，而我国HIE的死亡人数占新生儿死亡人数的28.6%[4]。国外的一项多中心研究还发现，HIE的病死率可高达42%[5]，且存活下来的中、重度HIE患儿中有近50%存在不同程度的智力、感觉、学习等障碍，以及癫痫、脑瘫等重大残疾[6]，严重影响了患儿的生活质量，并给家庭及社会带来了沉重的康复压力和经济负担。然而，HIE的发病机制复杂，目前尚无有效的治疗措施。
近年来，随着细胞工程技术的发展，具有多向分化与自我增殖潜能的间充质干细胞备受关注，尤其是来源于人脐血的间充质干细胞(human umbilical cord mesenchymal stem cells，hUC-MSCs)，具有来源丰富、成本低、易于采集及分离、无创伤、免疫原性低及不涉及伦理问题等优点，且国内多地已建有脐血干细胞库，保证了细胞移植的来源，但长期细胞移植仍受到成本高、免疫排斥及致瘤等问题的困扰[7-8]。目前多项研究表明，间充质干细胞主要通过其释放的外泌体发挥作用[9-11]，外泌体在治疗中枢神经系统疾病时可发挥抗炎、促进神经元生长[12-13]及神经突触重塑[14-15]等作用。与干细胞比较，外泌体易于保存，可避免细胞复苏、异常分化及致瘤等问题的困扰[16]。目前研究认为，在HIE的发病机制中，缺氧缺血导致的大量神经细胞凋亡是中枢神经系统损伤或神经后遗症的主要原因[17]。然而，hUC-MSCs来源的外泌体(hUC-MSCs-Exos)在HIE中的作用机制目前尚不明确，且多种给药方式均存在一定的不足：经静脉给药虽然方便快捷、创伤小，但实际进入脑内的外泌体量较少；侧脑室给药或脑内定点给药虽保证了进入脑内的外泌体量，但存在创伤大、不易操作、难以推广等问题。本研究采用Rice-Vannucci改良法[18]建立新生小鼠缺氧缺血性脑损伤(hypoxic ischemic brain damage，HIBD)模型，模拟新生儿缺氧缺血后出现的HIE脑内病理变化，并通过经腹腔及鼻腔两种不同的给药方式探讨hUC-MSCs-Exos对新生小鼠HIBD后神经行为学及脑组织损伤修复的影响，旨在为临床治疗HIE寻找更加安全有效、方便快捷且可行性强的治疗方式，从而减轻HIE患儿后遗症的康复压力及家庭经济负担。
1 材料与方法
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1.1 实验动物
1周龄SPF级BALB/c小鼠28只，雌雄不限，体重(4.5±0.6) g，购自成都达硕实验动物有限公司[实验动物生产许可证号：SYXK(川)2015-030]。小鼠饲养在光/暗周期12 h/12 h，温度(24±2) ℃，相对湿度37%~46%，自由摄食饮水的环境。定期打扫以保持环境干净、清洁、通风良好。本研究获甘肃省人民医院动物伦理委员会审批(2022-007)，动物饲养和实验操作符合国家和单位的相关规定。
1.2 主要试剂及仪器
hUC-MSCs、hUC-MSCs完全培养基(武汉普诺赛生命科技有限公司)；胎牛血清(江苏恩莫阿赛生物技术有限公司)；磷酸盐缓冲液(phosphate buffer saline，PBS；上海生工生物工程有限公司)；苏木精-伊红染液(武汉塞维尔生物科技有限公司)；中性树脂(上海白鲨生物科技有限公司)；甲苯胺蓝(上海如吉生物科技发展有限公司)；4,6-二脒基-2-苯基吲哚(4,6-diamidino-2-phenylindole，DAPI；5 μg/ml)染色液(北京雷根生物有限公司)；TUNEL试剂盒(瑞士Roche公司)；Western blotting及免疫沉淀(immunoprecipitation，IP)细胞裂解液、BCA蛋白浓度测定试剂盒(上海碧云天生物科技有限公司)；Immobilon-PSQ PVDF膜(美国Sigma-Aldrich公司)；PAGE凝胶快速制备试剂盒(上海雅酶生物科技有限公司)。超速离心机、透射电镜(日本Hitachi公司)；转轮式切片机(德国徕卡公司)；JT-12S自动组织脱水机(武汉俊杰电子有限公司)；BMJ-A型包埋机(常州郊区中威电子仪器厂)；RS36型全自动染色机(常州派斯杰医疗设备有限公司)；PHY-Ⅲ型病理组织漂烘仪(常州市中威电子仪器有限公司)；数字切片扫描仪(匈利亚3DHISTECH公司)。
1.3 hUC-MSCs-Exos的提取
1.3.1 hUC-MSCs的培养、鉴定
将装有hUC-MSCs的冻存管放入37 ℃水浴锅中，待冻存液融化，轻轻吹打转移至15 ml离心管中，加入冻存液3倍体积的新鲜培养基，37 ℃下250×g离心5 min，吸弃上清，加入新鲜培养基，转移至培养瓶中，置于37 ℃、5% CO2培养箱中孵育；待细胞生长融合达80%~90%时取出hUC-MSCs，PBS洗2次，加入孵温的胰酶，轻晃培养瓶，以使消化液完全浸润细胞；倒置显微镜下观察细胞形态控制消化终止时间，以1:3传代培养，传至第4代时收集细胞上清液，-80 ℃冻存备用。
1.3.2 hUC-MSCs-Exos的提取与鉴定
将-80 ℃冻存的细胞上清液于37 ℃速溶，在4 ℃下分次梯度2000×g离心30 min；取上清液，10 000×g离心45 min，去除较大的囊泡；取上清液，0.45 μm滤膜过滤，收集过滤液，100 000×g超速离心70 min；去除上清，用10 ml预冷的1× PBS重悬后，100 000×g超速离心70 min；去除上清，用100 μl预冷的1× PBS重悬后用于后续实验。其中20 μl用于电镜观察，10 μl用于蛋白浓度检测，10 μl用于粒径分析，50 μl用于蛋白表达检测，剩余外泌体于-80 ℃保存备用。采用透射电子显微镜观察外泌体形态和结构，BCA蛋白定量法检测外泌体蛋白浓度，纳米粒子跟踪分析器进行粒径分析，Western blotting检测外泌体表面标记蛋白TSG101的表达情况。
1.4 实验动物的分组、造模及干预
采用随机数字表法将28只小鼠分为假手术组(n=6)、模型组(n=6)、外泌体1组(经腹腔注射外泌体，n=8)及外泌体2组(经鼻腔滴入外泌体，n=8)。假手术组只分离左颈总动脉，不作结扎、缺氧等处理，其余各组采用Rice-Vannucci法[18]制备HIBD小鼠模型，小鼠出现行走平衡能力失常、翻转身体困难等缺氧缺血表现视为造模成功。外泌体1组、外泌体2组小鼠分别于造模成功后24 h内经腹腔注射或鼻腔滴入混有10 μl外泌体的100 μl PBS，假手术组及模型组小鼠分别经腹腔注射100 μl PBS。干预后7 d进行神经行为学评估(1 d内完成)，在评估完成后第2天处死小鼠，断头取脑，脑组织以4%甲醛溶液固定，石蜡包埋，经冷冻切片机进行连续冠状切片，厚度5 μm，行HE染色、甲苯胺蓝染色、TUNEL染色。
1.5 神经行为学评估
1.5.1 水平网格测试评估小鼠四肢抓握能力
采用文献[19]的方法，将小鼠置于100 cm×38 cm大小的悬挂网格状区域(网格开口2 cm×2 cm)自由爬行，记录并评估小鼠通过网格时后肢摔倒(即四肢无法抓住网线掉入网孔中)的次数，每只小鼠连续测试3次，每次间隔30 min，取平均值作为最终测试结果。
1.5.2 爬杆实验评估小鼠肢体运动协调能力
采用文献[20]的方法，将小鼠置于固定在木杆(长50 cm，直径1 cm)顶的软木球(直径25 cm)上，分别记录其从软木球上下来所需要的时间、爬完杆上半部所需要的时间、爬完杆下半部所需要的时间。评分标准：3 s内完成上述某一动作计1分；6 s内完成计2分；超过6 s完成计3分；记录每只小鼠完成上述所有动作的总得分。
1.6 HE染色
脑组织切片脱蜡至水，常规HE染色，梯度乙醇脱水，二甲苯透明，中性树脂封片，光学显微镜下观察。采用数字切片扫描仪进行图像采集，每张切片先于40倍放大倍数下观察全部组织及大体病变情况，再对选定区域在100倍和400倍放大倍数下观察具体病变。
1.7 甲苯胺蓝染色
取固定好的脑组织切片脱蜡至水；将其放入预热至50 ℃的1%甲苯胺蓝溶液中，56 ℃恒温染色20 min；用蒸馏水清洗，70%乙醇浸泡；95%乙醇分化；无水乙醇快速脱水；二甲苯透明、中性树脂封片。采用数字切片扫描仪进行图像采集，每张切片采集3张400倍图片进行尼氏小体计数。
1.8 TUNEL染色检测细胞凋亡情况
取固定好的脑组织切片脱蜡至水，纯化水浸泡5 min；柠檬酸微波修复8 min，PBS清洗3次；荧光TUNEL孵育液37 ℃孵育1 h，PBS洗3次；DAPI染核15 min，明胶封片。采用数字切片扫描仪进行图像采集，并对正常细胞和凋亡细胞进行计数，计算细胞凋亡率。细胞凋亡率(%)=凋亡细胞数/(正常细胞数+凋亡细胞数)×100%。
1.9 统计学处理
采用SPSS 22.0软件进行统计分析。计量资料均符合正态分布，以$\bar{x}±s$表示，多组间比较采用单因素方差分析，方差齐时，进一步两两比较采用LSD-t检验，方差不齐时，进一步两两比较采用Tamhane's T2检验。计数资料以例(%)表示，组间比较采用χ2检验。P<0.05为差异有统计学意义。
2 结果
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2.1 hUC-MSCs-Exos的鉴定
透射电子显微镜下可观察到数个形态完整、大小均一、类圆形的微囊泡小体(图1A)，其平均直径为123.8 nm(图1B)。Western blotting检测结果显示，hUC-MSCs-Exos特异性标志物TSG101表达阳性(图1C)。
2.2 各组小鼠神经行为学评估结果
与假手术组比较，模型组、外泌体1组、外泌体2组小鼠的水平网格测试中后肢掉落次数及爬杆实验评分均明显增高(P<0.05)；模型组、外泌体1组、外泌体2组小鼠水平网格测试中后肢掉落次数及爬杆实验评分比较差异均无统计学意义(P>0.05，表1)。
2.3 hUC-MSCs-Exos对小鼠脑组织病理损伤的影响
HE染色显示，假手术组小鼠脑组织软脑膜结构完整，由一层薄层的结缔组织构成，内含丰富的血管，未见明显炎性渗出；皮质区神经元细胞形态正常，未见明显细胞变性坏死、炎性细胞浸润或胶质细胞增生。模型组脑组织皮质区可见炎性细胞浸润和胶质细胞增生，神经元细胞呈片状坏死、变性，细胞质淡染，胞质胞核边界不清，胞核裂解，伴局部出血及血管扩张等病理改变。外泌体1组小鼠脑组织皮质区神经元片状坏死明显减少，部分可见神经元空泡变性及较多胶质细胞增生；外泌体2组小鼠脑组织皮质区未见神经元片状坏死，可见不同程度神经元变性及少量胶质细胞增生(图2)。
2.4 各组小鼠脑组织皮质区尼氏小体计数及细胞凋亡率比较
甲苯胺蓝染色显示，与假手术组比较，模型组、外泌体1组、外泌体2组小鼠脑组织皮质区神经元尼氏小体计数明显减少(P<0.05)；与模型组比较，外泌体1组、外泌体2组脑组织皮质区神经元尼氏小体计数明显增多(P<0.05)；与外泌体1组比较，外泌体2组脑组织皮质区神经元尼氏小体计数明显增多(P<0.05，图3、表2)。TUNEL染色显示，与假手术组比较，模型组、外泌体1组、外泌体2组小鼠脑组织皮质区细胞凋亡率明显升高(P<0.05)；与模型组比较，外泌体1组、外泌体2组小鼠脑组织皮质区细胞凋亡率明显降低(P<0.05)；与外泌体1组比较，外泌体2组小鼠脑组织皮质区细胞凋亡率明显降低(P<0.05，表2)。
3 讨论
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HIE是一种因围生期全身性低氧血症、脑血流低灌注引起脑缺氧缺血，且对新生儿脑细胞造成损害的神经系统疾病，是造成新生儿死亡和儿童永久性神经功能障碍如发育迟缓、智力障碍或脑瘫等的重要原因。HIE的发病机制尚不明确，且目前临床上采用的治疗措施如亚低温、高压氧、红细胞生成素、神经保护等[21-22]效果并不理想，故探索HIE的有效治疗方法仍然是围生期及新生儿医学的巨大挑战。随着近些年细胞工程的发展，间充质干细胞越来越受到关注。有研究发现，间充质干细胞主要通过旁分泌产生的细胞外囊泡即外泌体发挥其生物学功能[9-10]。外泌体作为细胞间信息交流的重要工具，参与多个信号通路的调节，可对受损组织发挥保护作用，目前的研究证实其对创伤性脑损伤、脊髓损伤、阿尔茨海默病、特发性帕金森病、癫痫等神经系统疾病均具有良好的组织修复作用[23-24]。有研究发现，外泌体对新生儿HIE脑损伤也有一定的修复及保护作用，尤其是来源更广的hUC-MSCs-Exos更受研究者的青睐，且不同给药方式与其修复效果密切相关[25]。目前采用的给药方式有侧脑室或脑实质内定向注射、静脉注射、腹腔注射，以及近几年探索的鼻腔滴入等。但脑内注射操作难度系数高，静脉注射易穿孔形成血肿或外渗。与前面几种方式比较，腹腔注射及鼻腔滴入较易操作，为此，本研究比较了腹腔注射及鼻腔滴入两种途径给予hUC-MSCs-Exos对HIBD的修复效果。水平网格测试和爬杆实验结果表明，采用两种给药方式的小鼠无论在四肢抓握还是运动协调方面均有一定程度的恢复，但与模型组相比差异无统计学意义，且两种给药方式间差异亦无统计学意义，可能与本次实验样本量小、给药次数不足及观察时间窗较短等有关，计划在后续实验中增加样本量、给药次数，并调整观察时间窗进一步研究。
HIE的病理基础是缺氧缺血导致的脑细胞水肿、坏死、出血，最易受损伤的区域为大脑深部灰质，其中足月儿多见于侧丘脑、苍白球、壳核后部、海马、脑干及感觉运动皮质区，而胎龄<36周的早产儿多发生在丘脑和脑干[26]。本研究中，模型组小鼠脑组织在光镜下可见片状坏死，胶质细胞增生，神经元变性坏死，细胞排列紊乱、结构不清、胞体肿胀、胞膜崩解，胞质外渗，胞核碎裂溶解，出血及血管扩张充血，与新生儿HIE的病理改变一致，提示造模基本成功。与模型组比较，外泌体组小鼠脑组织病理改变程度明显减轻，证实外泌体对HIBD具有确切的脑保护作用，与Luo等[27]及Xu等[28]的研究结果相符。肖升平等[29]的研究显示，间充质干细胞可通过血脑屏障定植于脑内；而官晓清等[30]及杨汉华等[31]报道，经腹腔注射及经鼻滴入间充质干细胞均对HIE所致的脑损伤具有保护作用。本研究发现，经两种方式给予hUC-MSCs-Exos对HIBD小鼠的脑损伤均具有明显的修复作用，与上述研究相符。此外，本研究还发现，外泌体2组小鼠脑组织病理改变程度较外泌体1组减轻，提示hUC-MSCs-Exos经鼻腔给药的脑保护作用明显优于腹腔注射，这可能与腹腔注射外泌体经腹膜进入血液循环后被代谢，从而使通过血脑屏障进入脑内的外泌体量减少有关。
神经细胞凋亡性损伤是新生儿缺氧缺血导致后期神经行为和(或)功能性障碍的根本原因，而充足的神经元是维持正常神经系统功能的重要前提。众多关于HIE发病机制的研究认为，氧化应激、免疫炎症反应、细胞凋亡等均参与了HIE的发病[17,32-34]，而关于间充质干细胞对HIE脑保护作用的研究发现，外泌体是其发挥作用的核心，可参与调控神经元凋亡，并减轻HIBD的脑损害[9-10,27-28]。尼氏小体可代表神经元功能的状态，细胞凋亡率则反映了神经元的受损程度。本研究中，外泌体组皮质区神经元尼氏小体计数较模型组明显增多，细胞凋亡率明显下降，表明hUC-MSCs-Exos可通过维持受损神经组织周围的神经元数量、减少神经元凋亡来减轻HIE对神经系统的损伤程度，与Li等[12]及Luo等[27]的研究一致。同时，本研究甲苯胺蓝染色及TUNEL染色结果也表明经鼻腔给予外泌体对HIBD的脑保护作用优于腹腔注射。
综上所述，本研究结果显示，hUC-MSCs-Exos对HIBD小鼠脑损伤具有明显的修复及神经保护作用，且经鼻腔给药对HIBD小鼠神经细胞凋亡的改善效果更明显，为未来临床上使用hUC-MSCs-Exos无创且高效治疗HIE奠定了一定的理论基础。但本研究仍存在一定的局限性，如未对治疗时间窗的选择进行研究，这也将是未来研究的方向和重点。
基金
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  • 甘肃省自然科学基金(22JR5RA689)
  • 甘肃省青年科技基金计划项目(22JR5RA701)
  • 甘肃省外科肿瘤分子诊断与精准治疗重点实验室项目(GSSZDSYS2020-10)
  • 甘肃省人民医院院内科研基金(20GSSY1-13)
文献
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参考文献 引证文献
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doi: 10.11855/j.issn.0577-7402.1084.2024.1118
  • 接收时间：2023-08-15
  • 首发时间：2025-11-10
  • 出版时间：2025-02-28
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  • 收稿日期：2023-08-15
  • 录用日期：2023-10-12
基金
Natural Science Foundation of Gansu Province(22JR5RA689)
甘肃省自然科学基金(22JR5RA689)
Gansu Youth Science and Technology Fund Project(22JR5RA701)
甘肃省青年科技基金计划项目(22JR5RA701)
Key Laboratory of Molecular Diagnosis and Precision Therapy of Surgical Tumor of Gansu Province(GSSZDSYS2020-10)
甘肃省外科肿瘤分子诊断与精准治疗重点实验室项目(GSSZDSYS2020-10)
Research Foundation of People's Hospital of Gansu Province(20GSSY1-13)
甘肃省人民医院院内科研基金(20GSSY1-13)
作者信息
    甘肃省人民医院/甘肃中医药大学第一临床医学院儿科，甘肃兰州 730030

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赛依帕，E-mail：
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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