CN112516168B - 用于干预应激性认知障碍的间充质干细胞 - Google Patents
用于干预应激性认知障碍的间充质干细胞 Download PDFInfo
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Abstract
本发明提供了表达FGF21和GLP1的间充质干细胞在制备治疗认知障碍，特别是应激导致的认知障碍的药物中的应用。
Description
技术领域
本申请涉及神经系统疾病治疗和细胞治疗领域，具体地，本申请提供了一种表达FGF21和GLP1的间充质干细胞在治疗应激性认知障碍药物中的应用。
背景技术
应激(Stress)是机体在对生存环境中多种不利因素适应过程中，实际或认知上的要求与适应和应付能力之间不平衡导致的身心紧张状态及其反应。应激反应对机体各系统产生广泛的影响，适度的应激可以提高人的认知能力，增强思维的灵活性，有助于启动机体应对应激源的适应性反应，但长期或强烈的应激则导致机体认知功能损伤。
应激所致认知功能损伤首先表现为对信息加工的影响，特别是对于记忆和注意力的影响。研究发现，应激所致机体神经内分泌水平的异常变化可降低机体的听觉和视觉注意力，并导致分散注意力任务操作成绩显著降低。学习能力的下降是应激所致认知功能损伤的一个显著特征。高负荷应激可抑制机体的空间学习、联想学习、情绪性学习等多种学习能力，学习能力的下降与应激机体肾上腺素水平的异常升高密切相关。目前应激性认识障碍的机制不清晰，且由于脑部存在血脑屏障，常规给药途径能够到达脑区的药物剂量有限，使得目前临床干预应激性认知障碍的药物极为稀缺。
发明内容
由于血脑屏障的存在，针对认知障碍目前无良好的干预手段，常规给药途径能够到达脑区的药物剂量有限，脑局部注射给药途径又增加了治疗的难度，导致现有干预手段多为治标不治本。本申请用间充质干细胞搭载两个本身对脑神经具有保护作用的基因(FGF21和GLP1)作为治疗和干预应激性认知障碍的手段，解决了以上难题且降低了给药次数。
申请人构建了FGF21和GLP1双基因修饰的间充质干细胞系(MSC-FG细胞)，对模型鼠尾静脉回输MSC-FG细胞，监测认知行为是否改善，检测海马区局部脑组织糖含量，检测异常代谢途径，最终通过对各项指标恢复情况的判定来确定MSC-FG对应激性认知障碍干预的有效性：结果表明FGF21和GLP1修饰的间充质干细胞能够显著改善和预防应激性认知障碍。
一方面，本申请提供了一种间充质干细胞在制备治疗应激性认知障碍的药物中的应用，其特征在于，所述间充质干细胞表达FGF21和GLP1。
进一步地，所述间充质干细胞为脂肪间充质干细胞。
进一步地，其中表达的FGF21蛋白序列为SEQ ID NO.1或者其变体。
进一步地，其中表达的CLP1蛋白序列为SEQ ID NO.3或者其变体。
进一步地，其中FGF21和/或GLP1与额外多肽融合。
进一步地，所述额外多肽选自免疫球蛋白Fc结构域、白蛋白结合多肽、转铁蛋白或其功能性片段。
进一步地，其中额外多肽为序列为SEQ ID NO.5的Fc片段。
进一步的，所述FGF21和GLP1由SEQ ID NO.2和SEQ ID NO.4编码。
进一步地，所述认知障碍为应激引起的认知障碍。
进一步地，所述药物剂型为注射剂。
本申请中的间充质干细胞包括各种来源的间充质干细胞，来源包括但不限于脂肪、脊髓、脐带、肌肉、粘膜等，优选脂肪来源的间充质干细胞。
本申请中的FGF21和GLP1基因和蛋白序列可以选择本领域中已知的人或哺乳动物FGF21和GLP1天然或变体基因和蛋白序列，包括但不限于Genbank、EMBL等数据库以及各国专利数据库中检索到的序列。
本申请中的变体是指与原蛋白或基因序列有一定的同一性，如99％以上，95％以上，90％以上，85％以上，80％以上，70％以上，并能实现相同或类似功能的蛋白或基因序列，这些序列本领域技术人员除了查阅已知文献和数据库获知外，也可以参考现有技术中的基因蛋白功能预测方法获得。
除间充质干细胞外，本申请的药物组合物中还可以包含其它本领域已知的治疗认知障碍的药物，包括但不限于镇静剂，神经营养补充剂，神经生长因子等。
除间充质干细胞外，本申请的药物组合物中还可以包含其它药学和细胞学上可接受的辅料，如培养液，溶剂，助溶剂，抗氧化剂，稳定剂，pH调节剂等，具体种类可参考CellTherapy:Stem Cell Transplantation,Gene Therapy and Cellular Immunotherapy,Cambridge,1996等细胞治疗领域著作。
本申请的药物可以为各种干细胞可用的/潜在可用的药物剂型，包括但不限于片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂等，优选剂型为注射剂。
除以上记载外，本发明主要优势还包括：
采用的MSC载体细胞具有多项分化潜能，能够通过血脑屏障定植于脑中，起到药物运输载体的功能，同时由于间充质干细胞可长期存活，可直接降低给药次数。另外，在结合FGF21和GLP1对缓解认知损伤的效果基础上，间充质干细胞能够通过分泌途径对生理性和病理性脑衰老进行系统性的干预，增强突触可塑性、提高认知功能，最终改善衰老小鼠脑衰老特征，改善AD模型鼠的病理特征。综上，MSC-FG作为应激性认识损伤的干预手段，可以解决现有治疗手段中存在的各种问题，通过多个方面共同作用从而改善应激导致的认知损伤情况。
附图说明
图1：pCDH-CMV-FGF21mut-GLP1Fc质粒图谱。
图2：MSC-FGF21mut-GLP1Fc基因表达验证：A：RT-QPCR在分子水平验证FGF21mut和GLP1Fc基因表达，B：ELISA在蛋白水平验证FGF21mut和GLP1Fc因子表达，C：WB在蛋白水平验证FGF21mut和GLP1Fc因子表达。
图3：慢性应激对小鼠体重的影响(6周后治疗)，Mean±SEM，n＝8，**代表P<0.01(Stress and Stress+MSC VS Con and Con+MSC)；
图4：外周血检测指标，Mean±SEM，n＝6，不同上标字母代表差异显著；
图5：海马区检测指标，Mean±SEM，n＝6，不同上标字母代表差异显著；
图6：前额叶皮层区检测指标，Mean±SEM，n＝6，不同上标字母代表差异显著；
图7：行为学检测——旷场实验，Mean±SEM，n＝8，*代表P<0.05,**代表P<0.01；
图8：行为学检测——Morris水迷宫，Mean±SEM，n＝8，*代表P<0.05,**代表P<0.01；
图9：小鼠脑免疫荧光染色检测MSC细胞在脑中定位；
图10：小鼠脑尼氏染色；
图11：Western Blot检测MSC-FGF21mut-GLP1Fc在海马和前额叶皮层作用的信号通路；
具体实施方式
实施例1构建具有报告基因的双启动子表达载体(pCDH-CMV-FGF21mut-GLP1Fc)
将现有载体pCDH-EF1-FGF21-T2A-GLP1进行FGF21基因突变，并换启动子、插入报告基因，以在后期追踪MSC细胞的定植。对FGF21基因进行突变是为了提高该因子的活性。构建好的载体命名为pCDH-CMV-FGF21mut-GLP1Fc，将构建好的载体进行大提，包装慢病毒，然后感染MSC细胞。实验步骤包括：
(1)载体：用BamHI和NotI双酶切载体pCDH-CMV-MCS-EF1-copGFP-T2A-Puro(购买自SBI公司)，3ug，37℃3h，直接纯化回收。
(2)设计引物：
CMV-BamHI-FGF21-F：gctagcgaattcgaatttaaatcggatccGCCACCATGGACTCG
IgG4Fc-NotI-R：gcgatcgcagatccttcgcggccgcTCATTTACCCGGAGACAGGGAGAGG
(3)PCR FGF21mut-GLP1Fc片段，模板pGS1-FGF21mut-GLP1(中美泰和合成)，模板100ng用Ex Taq酶，退火57℃
Primer F：CMV-BamHI-FGF21-F，Tm＝62℃
Primer R：IgG4Fc-NotI-R，Tm＝62℃
胶回收1261bp左右片段
(4)用中美泰和2X mix重组连接，载体和FGF21mut-GLP1Fc片段
(5)DH5a转化，Amp抗性
(6)以EF1通用引物PEF-F和申请人设计的pCDH-Down测序
(7)正确测序后保存菌种，大提质粒，质粒图谱如图1所示
其中，所述琼脂糖购自Biowest，DNA电泳marker购自天根生化科技(北京)有限公司，PCR扩增体系购自宝日医生物技术(北京)有限公司，DNA回收试剂盒购自天根生化科技(北京)有限公司，限制性内切酶BamHI和NotI购自NEB，T4 DNA连接酶购自普洛麦格(北京)生物技术有限公司，大肠杆菌E.coliDH5α感受态细胞购自天根生化科技(北京)有限公司，序列测定由北京擎科新业生物技术有限公司公司进行。
其中FGF21氨基酸序列为SEQ ID NO.1，核苷酸序列为SEQ ID NO.2；GLP1氨基酸序列为SEQ ID NO.3，核苷酸序列为SEQ ID NO.4；Fc片段氨基酸序列为SEQ ID NO.5，核苷酸序列为SEQ ID NO.6。
实施例2制备携带FGF21mut-GLP1Fc的重组慢病毒
(1)从液氮中取出1支冻存的293T细胞(购自ATCC)迅速放到37℃水浴中直至冰块消失，逐滴加入含有5ml预热培养基的15ml离心管中，1200rpm离心3min，弃上清，用293T培养基(10％FBS+1mM丙酮酸钠+2mM谷氨酰胺+1％非必需氨基酸+DMEM)重悬细胞接种至150mm培养皿中，37℃、5％CO2饱和湿度培养。培养过程中，待细胞汇合度达90％以上时，进行传代培养，弃去旧培养基，加入5ml灭菌PBS溶液，轻轻晃动，洗涤细胞后弃去PBS溶液，加入2ml0.25％Trypsin-EDTA消化液，消化1-2min直到细胞完全消化下来；加入含血清的培养基终止消化，细胞悬液1200rpm离心3min，离心所得细胞用培养基重悬。每个包被过的150mm培养皿细胞接种1.2×107个细胞用于包装慢病毒，37℃、5％CO2饱和湿度培养，20ml培养基/皿。
其中，293T培养基(10％FBS+1mM丙酮酸钠+2mM谷氨酰胺+1％非必需氨基酸+DMEM)来源于Gibco，PBS溶液购自Gibco，Trypsin-EDTA消化液购自Gibco。
(2)转染前2小时，将293T细胞培养基更换为18ml DMEM培养基，向A灭菌离心管中加入1ml预热的DMEM培养基，按照1:2:3的质量比例加入包膜质粒PMD.2G、包装质粒PSPAX和实施例1中制备的重组质粒的混合物，吹打混匀；向B灭菌离心管中加入1ml预热的DMEM培养基，然后加入162μl转染试剂PEI，混合均匀；A管和B管在室温下温育5min；将B管中的液体成滴的加入到A管中，混合均匀，室温孵育10min，以便形成DNA-转染试剂复合物。将DNA-转染试剂复合物转移至预先换液的293T细胞中，混匀，37℃、5％CO2饱和湿度培养。培养6-8h后吸弃含有转染混和物的培养基，每皿细胞加入20ml预热的含5％FBS的DMEM培养基，37℃、5％CO2饱和湿度培养。换液后分别在24h和48h收集上清液暂存储于4℃，并换20ml新鲜培养基。
其中，DMEM培养基购自Gibco，包膜质粒PMD.2G、包装质粒PSPAX购自Addgene，所述转染试剂PEI购自Polysciences，FBS购自Bioind。
(3)将上述收集的上清液4℃、3500rpm离心15min，弃沉淀，采用孔径为0.45μm的滤膜过滤。将过滤后的重组慢病毒与5X PEG混匀，4℃放置24小时后，4℃3000rpm离心30min，弃上清，将沉淀重悬至500μl DMEM培养基中。
实施例3制备FGF21mut-GLP1Fc修饰的间充质干细胞
采用混合胶原酶消化法分离培养脂肪间充质干细胞，具体方法如下：将吸脂手术吸取的健康成人脂肪组织，转移至50mL离心管中，加入PBS充分洗涤，1500rpm，离心5分钟，获取上层脂肪组织。按照1:1:1比例将I、I I及IV型胶原酶混合，配制为0.2％混合胶原酶，并按脂肪组织:胶原酶＝1:1的比例将脂肪组织加入混合胶原酶消化液中，置于37℃摇床中消化脂肪组织30分钟。将消化好的脂肪组织立刻加入10％FBS的α-MEM细胞培养基(购自Gibco)，1500rpm，离心10分钟，沉降细胞及组织团块。用α-MEM完全培养基重悬细胞，通过100μm孔径的尼龙网去除未消化的组织。将细胞接种于培养瓶，置于37℃，饱和湿度，5％CO2培养箱中静止培养。2天后，将未贴壁的细胞倒掉，PBS轻轻洗一遍，加入干细胞完全培养基，待细胞克隆长至80％融合时，0.05％胰酶消化传代至新培养瓶中。选择P3代细胞，用0.05％胰酶消化，PBS洗两遍后分别用小鼠抗人CD11b-PE、CD45-PE、HLA-DR-PE、CD73-PE、CD90-PE、CD105-PE、CD34-FITC及CD19-FITC抗体标记5×105个MSCs，室温避光放置30min，再用PBS洗两遍后，4％多聚甲醛固定，FACS检测。鉴定合格的细胞冻存于液氮罐中，用时复苏并做后期处理。
复苏预先冻存的P3代脂肪间充质干细胞至一个150mm培养皿，20ml无血清培养基37℃、5％CO2饱和湿度培养。待复苏细胞长满后，0.05％胰蛋白酶消化细胞，用含血清的培养基终止消化，细胞悬液800rpm离心5min，离心所得细胞用间充质干细胞无血清培养基(购自Bioind)重悬。每个150mm培养皿细胞接种2×106细胞，接种后的第二天吸取细胞的培养基弃掉，更换为无血清的α-MEM培养基，20ml培养基/皿，加入16μl聚凝胺Polybrene(购自Sigma)，按照40MOIs感染复数加入重组IL18-IL12慢病毒(滴度为1×108U/ml)，37℃、5％CO2饱和湿度培养7h。7小时后弃掉含有病毒的α-MEM培养基(购自Gibco)，更换为无血清培养基，37℃、5％CO2饱和湿度继续培养3天。
待细胞长满，收集细胞用RT-qPCR检测FGF21mut和GLP1Fc基因的表达，收取细胞上清用ELISA和WB检测FGF21和GLP1Fc因子的表达量(结果如图2所示)。剩余细胞用PBS清洗后，用0.05％胰蛋白酶消化细胞，用含血清的培养基终止消化，细胞悬液800rpm离心5min，离心所得细胞用无血清培养基重悬，按照1:6的传代比例进行传代，无血清培养基37℃、5％CO2培养3天，获得稳定表达FGF21mut和GLP1Fc基因的的重组间充质干细胞，命名为MSC-FGF21mut-GLP1(简写MSC-FG)。
实施例4动物实验
1、动物实验分组
采用的慢性应激动物实验模型是慢性温和不可预知应激(CUMS)动物模型(CUMS应激小鼠制备过程为：按照以下方式随机给予，潮湿17h、禁水+空瓶16h、禁食水23h、昼夜颠倒24h、束缚3h，相邻的2d干预方法不同，持续8周)：C57BL/6J雄性小鼠，体重18-20g，共32只小鼠，根据体重随机分为4组，每组8只老鼠：
①普通小鼠——对照组
②普通小鼠+MSC-FGF21mut-GLP1细胞干预
③CUMS应激小鼠
④CUMS应激小鼠+MSC-FGF21mut-GLP1细胞在CUMS应激建模前干预(应激后第6周干预，连续治疗3周)
MSC-FGF21mut-GLP1细胞采用尾静脉注射，在注射时间点每只小鼠每次注射1*106/100ul细胞，一共注射三次(分别在第6、7、8周进行注射)。
2、行为学检查指标、生理学指标和病理学指标检测
认知行为学检测：动物认知行为学检测指标采用旷场实验(情绪)和Morris水迷宫实验(学习能力)。
检测认知功能区的脑组织糖含量：取小鼠海马区组织，研磨后采用酶化学法检测脑组织局部组织糖含量——酶化学法(己糖激酶法葡萄糖检测试剂盒)
检测外周血中FGF21mut和GLP1因子含量：眼底静脉丛采血，用小鼠FGF21ELISA试剂盒和小鼠GLP1ELISA试剂盒检测。
检测认知功能区的脑组织局部FGF21和GLP1因子含量：取小鼠海马区组织，研磨后采用小鼠FGF21mut ELISA试剂盒和小鼠GLP1 ELISA试剂盒检测。
检测MSC-FGF21mut-GLP1细胞在认知功能区的定位和含量：取小鼠海马区组织，4％多聚甲醛固定，石蜡切片，GFP免疫组化染色追踪MSC细胞；取小鼠海马区组织，液氮冷冻，直接进行冰冻切片，荧光镜下直接观察MSC细胞含量和定位。
OCT包埋的冰冻切片的Nissl染色：PBS和4％多聚甲醛先后心脏灌注，取海马组织依次放入15％和30％蔗糖溶液梯度脱水沉底，OCT包埋，8μm厚度冰冻切片，0.1％TritonX-100常温处理，尼氏染液常温染色。
3、动物水平验证脑糖升高的机制及MSC-FGF21-GLP1干预效果
取海马区组织，研磨后采用小鼠Insulin ELISA试剂盒检测应急后脑组织局部Insulin含量；研磨后用含有1％cooktail的强RIPA提取细胞总蛋白，用WB检测胰岛素受体和胰岛素受体底物的含量。
4、主要结果解读
图3显示慢性应激(CUMS)可导致小鼠体重显著降低，给予MSC-FG治疗后，应激模型组小鼠体重有所恢复，但未见显著差异。
图4显示慢性应激(CUMS)可导致小鼠外周血胰岛素降低、FGF21含量上升、GLP1含量降低。给予MSC-FG治疗后，应激模型组小鼠胰岛素水平有所恢复，FGF21和GLP1含量升高。
图5显示慢性应激(CUMS)可导致小鼠海马区组织糖升高、胰岛素降低和GLP1含量降低。给予MSC-FG治疗后，应激模型组各检测指标均有所改善。
图6显示慢性应激(CUMS)可导致小鼠前额叶皮层区组织糖升高、胰岛素降低和GLP1含量降低。给予MSC-FG治疗后，应激模型组各检测指标均有所改善。
图7显示慢性应激小鼠旷场中的探索行为减少，活跃程度下降，即出现情绪调节障碍，焦虑水平上升，给予MSC-FG治疗后，可显著改善该症。
图8显示慢性应激小鼠在学期训练期的平均潜伏期显著增加，穿越平台的次数显著减少，即获得空间线索信息的能力下降，学习能力有所下降，空间记忆能力受损，对空间线索信息的保持和提取能力下降，给予MSC-FG治疗后，可显著改善该症状。
图9显示用于干预应激性认知障碍的MSC-FG细胞可以定植到脑中，特别是血脑屏障周围。在慢性应激小鼠的脑中，MSC-FG还定植于其它受损部位。
图10显示MSC-FG干预后，可以增加海马区尼氏小体的数量。
图11显示MSC-FG可以通过改善应激个体中胰岛素抵抗情况来改善其应激性认知障碍。
序列表
<110> 中国人民解放军军事科学院军事医学研究院
<120> 用于干预应激性认知障碍的间充质干细胞
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gactccagtc ctctcctgca attcgggggc caagtccggc aggtgtacct ctacacagat 60
gatgcccagc agacagaagc ccacctggag atcagggagg atgggacggt ggggggcgct 120
gctgaccaga gccccgaaag tctcctgcag ctgaaagcct tgaagccggg agttattcaa 180
atcttgggag tcaagacatc caggttcctg tgccagcggc cagatggggc cctgtatgga 240
tcgctccact ttgaccctga ggcctgcagc ttccgggagc ggcttcttga ggacggatac 300
aatgtttacc agtccgaagc ccacggcctc ccgctgcacc tgccagggaa caagtcccca 360
caccgggacc ctgcaccccg aggaccagct cgcttcctgc cactaccagg cctgcccccc 420
gcactcccgg agccacccgg aatcctggcc ccccagcccc ccgatgtggg ctcctcggac 480
cctctgagca tggtgggagg ctcccagggc cgaagcccca gctacgagtc c 531
<210> 3
<211> 51
<212> PRT
<213> 人(human)
<400> 3
Met Arg Ala Leu Leu Ala Arg Leu Leu Leu Cys Val Leu Val Val Ser
1 5 10 15
Asp Ser Lys Gly His Gly Glu Gly Thr Phe Thr Ser Asp Val Ser Ser
20 25 30
Tyr Leu Glu Glu Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys
35 40 45
Gly Gly Gly
50
<210> 4
<211> 153
<212> DNA
<213> 人(human)
<400> 4
atgagagccc tgctggcgcg cctgcttctc tgcgtcctgg tcgtgagcga ctccaaaggc 60
catggcgaag ggacctttac cagtgatgta agttcttatt tggaagagca agctgccaag 120
gaattcattg cttggctggt gaaaggcggc gga 153
<210> 5
<211> 229
<212> PRT
<213> 人(human)
<400> 5
Ala Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
1 5 10 15
Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
20 25 30
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
35 40 45
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
50 55 60
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
65 70 75 80
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
85 90 95
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
100 105 110
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
115 120 125
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
130 135 140
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
145 150 155 160
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
165 170 175
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
180 185 190
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
195 200 205
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
210 215 220
Ser Leu Ser Leu Gly
225
<210> 6
<211> 687
<212> DNA
<213> 人(human)
<400> 6
gctgagtcca aatatggtcc cccatgccca ccctgcccag cacctgaggc cgccggggga 60
ccatcagtct tcctgttccc cccaaaaccc aaggacactc tcatgatctc ccggacccct 120
gaggtcacgt gcgtggtggt ggacgtgagc caggaagacc ccgaggtcca gttcaactgg 180
tacgtggatg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagttcaac 240
agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaacggcaag 300
gagtacaagt gcaaggtctc caacaaaggc ctcccgtcct ccatcgagaa aaccatctcc 360
aaagccaaag ggcagccccg agagccacag gtgtacaccc tgcccccatc ccaggaggag 420
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 480
gccgtggagt gggaaagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 540
ctggactccg acggctcctt cttcctctac agcaggctaa ccgtggacaa gagcaggtgg 600
caggagggga atgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacaca 660
cagaagagcc tctccctgtc tctgggt 687
Claims (3)
1.间充质干细胞在制备治疗慢性不可预知应激引起的认知障碍的药物中的应用，其特征在于，所述间充质干细胞表达FGF21和GLP1；其中所述间充质干细胞为脂肪间充质干细胞；其中表达的FGF21蛋白序列为SEQ ID NO.1；其中表达的GLP1蛋白序列为SEQ ID NO.3；其中GLP1与免疫球蛋白Fc结构域融合；其中免疫球蛋白Fc结构域为序列为SEQ ID NO.5的Fc片段。
2.根据权利要求1所述的应用，所述FGF21和GLP1由SEQ ID NO.2和SEQ ID NO.4编码。
3.根据权利要求1或2所述的应用，其中所述药物剂型为注射剂。
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| Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory;Michael A van der Kooij et al.;《Proc Natl Acad Sci U S A》;20181023;第E10187-E10196页 * |
| Role of central glucagon-like peptide-1 in stress regulation;Sriparna Ghosal et al.;《Physiol Behav》;20131002;第201-207页 * |
| Roles of fibroblast growth factor 21 in the control of depression-like behaviours after social defeat stress in male rodents;Naoki Usui et al.;《J Neuroendocrinol》;20210809;文献号:e13026 * |
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