CN116077530A - 预处理的人羊膜上皮细胞在制备治疗和/或预防炎症疾病药物中的应用 - Google Patents
预处理的人羊膜上皮细胞在制备治疗和/或预防炎症疾病药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种预处理的人羊膜上皮细胞在制备治疗和/或预防炎症疾病药物中的应用，其预处理是采用促炎因子培养人羊膜上皮细胞。经过促炎因子预处理的人羊膜上皮细胞能够显著抑制炎症疾病，这可能是通过调节Th17/Treg细胞比例平衡而实现。
Description
技术领域
本发明涉及生物医药技术领域，尤其是涉及一种预处理的人羊膜上皮细胞在制备治疗和/或预防炎症疾病药物中的应用。
背景技术
免疫引发的炎症性事件是许多慢性炎症性疾病的重要原因，其中长时间的炎症可引起组织破坏，并可导致被感染的器官大幅损伤并最终衰竭。在很多情况下，这些疾病的确切病因是未知的。这些疾病包括自身免疫疾病，其中，尽管不了解该疾病的确切致病特征，但是已知炎症性和组织破坏性方面是由于对自身组织的不当的免疫应答引起的。涉及多个器官的病况包括例如系统性红斑狼疮(SLE)和硬皮病。其他类型的自身免疫疾病可涉及特定的组织或器官，例如胃肠道(例如，克罗恩氏病和溃疡性结肠炎(UC))。
溃疡性结肠炎是一种伴有免疫反应紊乱的慢性非特异性炎症性疾病。临床上目前治疗UC的药物为常规使用的激素类药物，存在明显的不良反应或疗效有限。因此，我们需要寻找其他更有效、更安全的药物。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此，本发明提出一种预处理的人羊膜上皮细胞在制备治疗和/或预防炎症疾病药物中的应用。
根据本发明的第一方面实施例提供一种预处理的人羊膜上皮细胞在制备治疗和/或预防炎症疾病药物中的应用，所述预处理是采用促炎因子培养人羊膜上皮细胞。
根据本发明实施例的应用，至少具有如下有益效果：
经过促炎因子预处理的人羊膜上皮细胞(human amniotic epithelial cells,hAECs)能够显著抑制炎症疾病，这可能是通过调节Th17/Treg比例平衡而实现。
根据本发明的一些实施例，所述促炎因子包括IFN-γ和TNF-α。采用IFN-γ和TNF-α预处理的人羊膜上皮细胞(Pretreated-human amniotic epithelial cells,Pre-hAECs)能够显著抑制葡聚糖硫酸钠(Dextran sodium sulfate，DSS)诱导的小鼠急性溃疡性结肠炎。
根据本发明的一些实施例，所述IFN-γ的浓度为0.08～20ng/mL。
根据本发明的一些实施例，所述TNF-α的浓度为0.08～20ng/mL。
根据本发明的一些实施例，所述预处理的人羊膜上皮细胞用于降低TH17细胞的含量。
根据本发明的一些实施例，所述预处理的人羊膜上皮细胞用于增加Treg细胞的含量。
根据本发明的一些实施例，所述炎症疾病包括由TH17细胞和Treg细胞诱导的炎症疾病。
根据本发明的一些实施例，所述炎症疾病包括但不限于骨质疏松、多发性硬化、风湿性关节炎、系统性红斑狼疮、急性溃疡性结肠炎。
根据本发明的一些实施例，所述炎症疾病包括急性溃疡性结肠炎。
根据本发明的一些实施例，所述预处理的人羊膜上皮细胞通过如下步骤制得：
当人羊膜上皮细胞长至70％～80％融合时，吸取细胞培养上清，用DPBS清洗两遍，加入促炎因子培养细胞24～48h，获得预处理的人羊膜上皮细胞。
根据本发明的一些实施例，所述人羊膜上皮细胞为第一代至第五代中任意一代。
根据本发明的一些实施例，从生产后废弃的人胎盘上剥离羊膜组织，经过特定处理后，获得hAECs。从羊膜组织首次消化分离培养的hAECs定义为P0代，此后每传代一次，代次增加1，即第一代表示为P1，以此类推。
根据本发明的一些实施例，所述药物包括药学上可接受的辅料。
根据本发明的一些实施例，所述辅料包括缓释剂、填充剂、粘合剂、润湿剂、崩解剂、吸附载体、吸收剂、表面活性剂或润滑剂中的至少一种。
根据本发明的一些实施例，所述药物的剂型包括溶液、悬液、乳剂、丸剂、片剂、胶囊、粉末或缓控释制剂中的至少一种。
本发明的其它特征和优点将在随后的说明书中阐述，并且，部分地从说明书中变得显而易见，或者通过实施本发明而了解。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1是hAECs的细胞特性图；其中A为人胎膜横断面的H&E染色图；B为P2 hAECs体外培养细胞形态图；C为hAECs细胞表面标记表达的流式结果的数据分析，以平均数±标准差表示(n＝5)；D为hAECs细胞表面标记表达流式检测结果(n＝5)；
图2是IFN-γ和TNF-α预处理对hAECs的影响图；其中，A为不同浓度IFN-γ和TNF-α预处理前后hAECs的形态。B、C为不同浓度IFN-γ和TNF-α预处理对hAECs炎症相关基因表达水平的影响；D、E为20ng/mL IFN-γ和TNF-α预处理后，WB法检测hAECs中IDO蛋白的表达；F为高效液相色谱法测定预处理24h和48h后hAECs中的色氨酸(Tryptophan)和犬尿氨酸(kynurenine)水平；G为20ng/mL IFN-γ和TNF-α预处理后hAECs的细胞增殖结果；*P<0.05，**p<0.01，***p<0.001，n＝3；
图3是DSS诱导UC小鼠模型构建图；其中，A为DSS诱导UC小鼠模型构建；B为对小鼠结肠组织进行苏木精和伊红(H&E)染色以确定疾病严重程度。组织切片采用pannoricdesk、P-MIDI、P250、P1000扫描；照片由Caseviewer 2.3获取。比例尺为500μm；C为小鼠体重变化图；D为疾病活性指数图；每组4～6只小鼠。结果以平均数±标准差表示。*p<.05，**p<.01，***p<.001；
图4为DSS-UC小鼠治疗结果图；结肠炎严重程度的评估图；其中，A为移植治疗具体策略；B为各组小鼠体重变化图；C为各组疾病活性指数图；D、E为各组小鼠结肠及结肠长度图；数据表示为平均数±标准差，n＝6，*p<0.05，**p<0.01，***p<0.001；
图5为各组UC小鼠结肠的组织学评分及MPO评分结果图：其中，A为各组小鼠的结肠组织HE染色结果，放大倍数为100×，比例尺为500μm，黑色框代表结肠上皮典型的病理学改变；B为各组小鼠结肠组织切片的组织病理学评分(n＝3)，组织病理学评分为由两名独立的病理学家以盲法严格按照评分标准进行；C为各组小鼠结肠组织MPO活性结果图(n＝6)；数值均以平均数±标准差表示。**P<0.01,***P<0.001；
图6为Pre-hAECs治疗后DSS-UC小鼠脾脏Th17和Treg细胞比例结果图；其中，A为Th(CD4+T细胞)的百分比；B为treg(CD4+CD25+FoxP3+T细胞)的百分比；C为Th1(CD4+IFN-γ+T细胞)的百分比；D为Th17(CD4+IL-17+)百分比。每组n＝6-8。数据表示为平均数±标准差。*p<0.05，**p<0.01，***p<0.001；
图7为Pre-hAECs调节人CD4+细胞分化的结果图：其中，A为Th1细胞比例变化图；B为Th2细胞比例变化图；C为Th17细胞比例变化图；D为Treg变化图；数值均以平均数±标准差表示，n＝4，*P<0.05,**P<0.01,***P<0.001。
具体实施方式
以下是本发明的具体实施例，并结合实施例对本发明的技术方案作进一步的描述，但本发明并不限于这些实施例。
本发明所采用的试剂、方法和设备，如无特殊说明，均为本技术领域常规试剂、方法和设备。
实施例
细胞鉴定：
采用流式细胞检测仪方法对分离获得的细胞进行表面标记表达的检测，建立细胞质控标准。待细胞长至80％左右后，将其消化并计数，以1×105个细胞/管为宜，按说明加入抗体后4℃避光孵育30min。孵育结束1200rpm，离心5min。每管以300uL至400μL DPBS重悬后上机。鉴定指标如下：CD326、CD90、CD105、SSEA4、HLA-G、HLA-DR、CD73、CD34及CD45。结果如下(图1)：
A：人胎膜横断面的H&E染色图。
B：体外培养的P2 hAECs细胞形态图：细胞呈上皮细胞的鹅卵石样形态，单层贴壁生长。
C、D：细胞表面标记流式检测结果；阳性细胞表达率分别为：CD326+为98.84％±0.18、CD90+为53.94％±2.9、CD105为99.86％±0.02、SSEA4+为85.64％±5.6、HLA-G+为77.5％±4.12、CD73+为99.86％±0.02，不表达HLA-DR、CD34及CD45，n＝5。
结果提示：成功分离得到具备低免疫原性的hAECs细胞。
细胞预处理：
hAECs(P2)细胞长至80％融合时，微量移液器小心吸取细胞培养上清，用DPBS清洗两遍，加入H-DMEM+10％FBS+IFN-γ+TNF-α的培养体系培养细胞24h，即获得Pre-hAECs。结果以平均值±标准差表示，n＝3，*P<0.05；**p<0.01，***p<0.001。结果如下(图2)：
A：预处理前后hAECs的体外培养细胞形态不受影响。
B、C：预处理影响hAECs炎症相关基因表达水平：随着IFN-γ和TNF-α浓度的增加，免疫抑制相关基因(如IDO、COX-2和TGFβ)的表达水平呈浓度依赖性增加。当IFN-γ和TNF-α浓度为20ng/mL时，促炎因子相关基因TNF-α、IFN-β和IL-6上调。
D、E：预处理后，hAECs中IDO蛋白的表达显著升高。
F：预处理后hAECs中的色氨酸和kynurenine水平显著升高。
G：预处理不影响hAECs的细胞增殖能力。
DSS诱导UC小鼠模型的构建：
UC小鼠模型构建：6至7周龄体重相似的C57BL/6雌性小鼠适应性喂养1周后，除对照组给予蒸馏水以外，其余各组均连续7天采用自由饮水的方式给予含4％(w/v)葡聚糖硫酸钠(DSS)的蒸馏水，期间随时观察结肠炎的发展。建模期间，每日记录小鼠体重、大便黏稠度及大便潜血情况计算疾病活动指数(DAI指数)以评估模型是否建立成功。具体评价指标如下：
1)疾病活跃指数评分(Disease Activity Index,DAI score)
从三个方面进行评估打分，分别为体重、粪便粘稠度、粪便潜血等指标，DAI评分为三个指标之和。
表1.DAI评分细则
2)组织学变化评分
组织学变化评分为上述各指标之和，在急性结肠炎模型中淋巴结形成不做评分。组织学分析的标准方法为HE染色。
表2.组织学变化评分
3)结肠长度
急性结肠炎模型中，第8天可检测到结肠长度缩短；慢性结肠炎模型中，结肠长度缩短更加明显。
总结：通常出现体重减轻、稀便、腹泻、血便或粪便潜血、溃疡可视为DSS药物有效。每组4～6只小鼠，结果以平均值±标准差表示。*p<.05，**p<.01，***p<.001。造模评估结果如下(图3)：
A：小鼠体貌特征：模型组小鼠(DSS-UC-小鼠)随着造模天数的增加，逐渐出现不同程度的体貌特征，如：毛色黯淡无光，蜷缩不喜动，反应迟钝及大便不成形甚至肛门周围出现黏液样血便，造模后期，饲养笼出现明显大便黏稠附着现象。
B：小鼠结肠组织形态：结肠黏膜上皮脱落明显，肠壁增厚，腺体减少，腔面呈溃烂样且伴大量炎症细胞浸润。
C：小鼠体重变化：正常组小鼠体重逐日增加，模型组小鼠体重随造模时间逐日呈现负增长。
D：小鼠疾病指数(DAI)变化：模型组小鼠于造模第4-5天出现明显稀便甚至血便，DAI指数与日俱增。
综上，模型组小鼠的各个疾病相关指标出现明显DSS诱导的急性UC病理特征，提示模型构建成功。
Pre-hAECs移植治疗UC小鼠：
UC小鼠模型建立第1天后：①hAECs治疗组(hAECs+DPBS)：腹腔注射含3×10^6hAECs的DPBS，注射体积500uL；②Pre-hAECs治疗组(Pre-hAECs+DPBS)：腹腔注射含3×10^6Pre-hAECs的DPBS，注射体积500uL；③模型组(DSS+DPBS)：仅注射DPBS,注射体积500uL；④正常对照组(Control+DPBS)：仅注射DPBS,注射体积500uL。治疗期间每日记录小鼠体重、大便黏稠度及大便潜血情况计算疾病活动指数(DAI指数)。实验结束，收集小鼠脾脏、结肠组织用于后续研究。结果以平均值±标准差表示。n＝6，*p<.05，**p<.01，***p<.001。实验结果如下(图4)：
A：移植治疗具体策略图示。
B：体重变化：与对照组(Control+DPBS)相比，模型组(DSS+DPBS)小鼠显示出明显的体重减轻，而Pre-hAECs治疗组(Pre-hAECs+DPBS)缓解了体重减轻的症状。
C：DAI变化：Pre-hAECs治疗组DAI显著降低。
D、E：小鼠结肠长度：模型组结肠平均5.32±0.12cm，Pre-hAECs治疗组结肠长6.08±0.08cm，结果有统计学差异(P<0.001)。
结果为：Pre-hAECs治疗可以抑制小鼠结肠缩短，改善小鼠体重降低以及降低疾病活动指数从而改善急性UC小鼠的疾病症状。
Pre-hAECs降低急性UC小鼠结肠组织学评分：
使用HE染色和评估结肠组织的组织病理学变化，进一步分析结肠组织MPO活性，评价结肠炎症的严重程度。数值均以平均数±标准差表示，n＝3-6，**P<0.01,***P<0.001。结果显示(图5)：
A：结肠结构HE染色结果：模型组表现出严重的粘膜下增厚，隐窝损害和黏膜及黏膜下层炎性细胞浸润的典型病理表现。Pre-hAECs治疗组表现出更加完整的结肠结构，没有明显的溃疡形成，炎性细胞浸润较少。
B：结肠组织病理学评分：Pre-hAECs治疗组评分下降。各组评分分别为：Control组0.54±0.103,模型组6.68±0.47,hAECs治疗组5.66±0.23,Pre-hAECs治疗组4.5±0.14。
C：各组小鼠结肠MPO活性结果：MPO活性提示中性粒细胞的募集，反应炎症活性程度。与模型组相比，hAECs和pre-hAECs治疗均抑制了结肠组织MPO活性的升高，但Pre-hAECs治疗组(0.098±0.006)的抑制作用较hAECs治疗组(0.122±0.006)更为显著。提示，提示Pre-hAECs具备更显著地降低小鼠结肠组织MPO活性的治疗作用。
结果表明：与hAECs治疗相比，Pre-hAECs移植治疗可以更显著改善UC小鼠的结肠炎症状态，并可显著降低结肠组织的MPO活性。
Pre-hAECs可以显著降低UC小鼠脾脏中Th17/Treg细胞的比例：
Th1和Th17促进结肠炎，而Treg在结肠炎的发展中具有保护作用。采用流式细胞仪对小鼠脾脏中脾脏Th17和Treg细胞比例进行检测。数据表示为平均数±标准差，n＝6-8，*p<0.05，**p<0.01，***p<0.001。结果显示(图6)：
A：各组间Th1(CD4+)细胞百分比没有差异。
B：Pre-hAECs治疗组Treg(CD4+CD25+FoxP3+T细胞)的百分比升高。
C：各组间Th1(CD4+IFN-γ+T细胞)的百分比没有差异。
D：Pre-hAECs治疗组Th17(CD4+IL-17+)百分比降低。
结果提示：Pre-hAECs处理显著降低了Th17的比例，促进了Treg细胞的增加，最终降低Th17/Treg细胞的比例。
体外实验验证Pre-hAECs对人CD4+细胞分化的调节作用：
从人外周血中通过梯度离心分离PBMC，采用磁珠分选获得纯化CD4+细胞，再与Pre-hAECs行体外共培养，检测细胞类型的分化。数值均以平均数±标准差表示，n＝4，*P<0.05,**P<0.01,***P<0.001。结果如下(图7)：
A：hAECs处理和Pre-hAECs处理都显著抑制了Th1细胞比例。
B：Pre-hAECs处理显著抑制了Th2细胞比例。
C：Pre-hAECs处理显著抑制了Th17细胞比例。
D：Pre-hAECs处理显著促进了Treg的增加。
结果证明了Pre-hAECs处理对T细胞亚群的调节作用。
综上，经IFN-γ和TNF-α预处理的hAECs(Pre-hAECs)可以增强hAECs的治疗效果和有用性，并显著抑制DSS诱导的小鼠结肠炎，这可能是通过调节Th17/Treg平衡而实现。Pre-hAECs可能为急性溃疡性结肠炎的治疗提供一种新的、更有效和实用的治疗方案。
上面结合本发明实施例作了详细说明，但本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。
Claims (10)
1.一种预处理的人羊膜上皮细胞在制备治疗和/或预防炎症疾病药物中的应用，其特征在于，所述预处理是采用促炎因子培养人羊膜上皮细胞。
2.根据权利要求1所述的应用，其特征在于，所述促炎因子包括IFN-γ和TNF-α。
3.根据权利要求2所述的应用，其特征在于，所述IFN-γ的浓度为0.08～20ng/mL。
4.根据权利要求2所述的应用，其特征在于，所述TNF-α的浓度为0.08～20ng/mL。
5.根据权利要求1所述的应用，其特征在于，所述预处理的人羊膜上皮细胞用于降低TH17细胞的含量。
6.根据权利要求1所述的应用，其特征在于，所述预处理的人羊膜上皮细胞用于增加Treg细胞的含量。
7.根据权利要求1所述的应用，其特征在于，所述炎症疾病包括由TH17细胞和Treg细胞诱导的炎症疾病。
8.根据权利要求1所述的应用，其特征在于，所述预处理的人羊膜上皮细胞通过如下步骤制得：
当人羊膜上皮细胞长至70％～80％融合时，吸取细胞培养上清，用DPBS清洗两遍，加入促炎因子培养细胞24～48h，获得预处理的人羊膜上皮细胞。
9.根据权利要求8所述的应用，其特征在于，所述药物包括药学上可接受的辅料。
10.根据权利要求9所述的应用，其特征在于，所述辅料包括缓释剂、填充剂、粘合剂、润湿剂、崩解剂、吸附载体、吸收剂、表面活性剂或润滑剂中的至少一种。
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