CN117122668A - 一种具有改善呼吸系统感染作用的全阵列细胞因子及其制备方法 - Google Patents
一种具有改善呼吸系统感染作用的全阵列细胞因子及其制备方法 Download PDFInfo
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Abstract
本发明提供一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，全阵列细胞因子包括FGF、G‑CSF、GM‑CSF、IFN‑γ、IL‑1β、IL‑1ra、IL‑2、IL‑4、IL‑5、IL‑6、IL‑7、IL‑8、IL‑9、IL‑10、IL‑12p70、IL‑13、IL‑15、IL‑17A、IP‑10、MCP‑1/MCAF、MIP‑1α、MIP‑1β、PDGF‑BB、RANTES、TNF‑α、VEGF、EGF、HGF，本发明制得的全阵列细胞因子具有良好的改善呼吸系统感染的作用。
Description
技术领域
本发明涉及细胞因子提取技术领域，特别涉及一种具有改善呼吸系统感染作用的全阵列细胞因子及其制备方法。
背景技术
间充质干细胞(MSC)是属于中胚层的，具有高度自我更新能力和多向分化潜能的多能干细胞。广泛存在于全身多种组织中，可在体外培养扩增，并能在特定条件下分化为神经细胞、成骨细胞、软骨细胞、肌肉细胞、脂肪细胞等。此外，间充质干细胞还具有强大的分泌能力，其分泌的细胞因子可以促进其它细胞增殖、修复受损组织、调节免疫系统、神经系统、抑制炎症等。正因如此，干细胞产生的生长因子被广泛应用于组织再生、免疫调节等领域。由于脐带中含有大量的间充质干细胞，且采集过程不会对供体造成任何损伤，所以脐带间充质干细胞的生长因子被广泛使用。例如专利CN113662967A提供了一种脐带干细胞裂解液治疗卵巢衰老方法；专利CN110448682A提供了一种使用干细胞裂解液治疗湿疹的方法等。本专利详细阐述了一种脐带间充质干细胞全阵列细胞因子的提取方法，以及使用脐带间充质干细胞全阵列细胞因子治疗COVID-19引起的呼吸系统感染的方法。
发明内容
鉴于此，本发明提出一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，解决上述问题。
本发明的技术方案是这样实现的：
一种具有改善呼吸系统感染作用的全阵列细胞因子，全阵列细胞因子包括FGF、G-CSF、GM-CSF、IFN-γ、IL-1β、IL-1ra、IL-2、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-12p70、IL-13、IL-15、IL-17A、IP-10、MCP-1/MCAF、MIP-1α、MIP-1β、PDGF-BB、RANTES、TNF-α、VEGF、EGF、HGF。
一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，包括以下步骤：
(1)脐带组织采用组织块贴壁法分离培养脐带间充质干细胞，得到原代细胞；
(2)细胞传代：原代细胞汇合度达到80％～90％时传代，收集第5代细胞培养上清液，冻干，得到传代细胞；
(3)细胞复融：将传代细胞在37℃水浴复融，细胞悬液用10倍体积的生理盐水洗涤一次后计数，离心，弃上清，得到复融后的细胞；
(4)细胞因子提取：将复融后的细胞采用注射用水重悬，将重悬细胞在23-27℃静置10-15min，再将重悬细胞浸入液氮中，得到冻结后的重悬细胞，冻结后的重悬细胞放入水浴锅中复融，复融后的重悬细胞浸入液氮中，重复冻融2-5次，收集上清液，过滤，制得全阵列细胞因子。
进一步的，步骤(2)中，细胞传代培养基包括基础培养基、纤粘连蛋白、胰岛素、丙酮酸钠、葡萄糖和甘醇酸。
进一步的，所述基础培养基为DMEM培养基。
进一步的，所述纤粘连蛋白8-12μg/mL、胰岛素13-17ng/mL、丙酮酸钠180-200mg/L、葡萄糖2-4g/L。
进一步的，所述甘醇酸浓度为13-17μM。
本发明传代培养基中组分合理配比，使原代细胞能够快速增殖分裂，能够诱导原代细胞分泌目标细胞因子，本发明传代培养基中甘醇酸不仅能加快细胞的增殖还能够增加细胞的黏着性，避免细胞产生机械损伤，本发明获得的第五代细胞细胞活力更好，稳定性更高。
进一步的，步骤(1)中，将脐带组织剪至1-3mm3，将剪碎后的脐带组织加入传代培养基中进行培养。
进一步的，所述传代培养基包括基础培养基、胰岛素、胰高糖素、链丝菌蛋白酶、亚硒酸钠、天门冬氨酸、丝氨酸、甘氨酸、胆固醇和纤粘连蛋白。
进一步的，所述基础培养基为SFM培养基，胰岛素25-35μg/mL、链丝菌蛋白酶0.4-0.6g/L、亚硒酸钠13-17μg/mL、天门冬氨酸7.5mg/L～11.5mg、丝氨酸8mg/L～14mg/L、甘氨酸6mg/L～8mg/L、胆固醇25-45mg/L和纤粘连蛋白23-27μg/mL。
本发明提取原代细胞培养基采用SFM培养基、胰岛素、胰高糖素、链丝菌蛋白酶、亚硒酸钠、天门冬氨酸、丝氨酸、甘氨酸、胆固醇和纤粘连蛋白制得。由于本发明提取原料为脐带组织，因此本发明原代细胞培养基不涉及血清添加物，可以减少血清中未知组分的干扰和血源性污染，减少血清的添加会导致细胞增长过慢、容易受到机械和化学因素的损伤、细胞增殖过慢等问题出现。本发明中通过SFM培养基和补充因子混合，能够促进细胞RNA、蛋白质和脂肪酸合成，防止细胞凋亡。合理的营养成分能够满足细胞生长的营养需求，提高目的产物的表达量。
进一步的，全阵列细胞因子冻干剂采用雾化给药的方式进行给药。
进一步的，根据全阵列细胞因子加入0.1％的甘露醇进行冻干。
进一步的，冻干参数为在-30℃下预冻5h，调整冷冻干燥机温度-60℃，真空度为3Pa下冻干10h。
与现有技术相比，本发明的有益效果是：
本发明采用干细胞全阵列因子作为雾化药物，因其含有丰富的生长因子、抗炎因子，可快速起到消炎止咳的作用，并且促进肺部及呼吸道细胞更新，快速修复肺部及呼吸道生理功能。
具体实施方式
为了更好理解本发明技术内容，下面提供具体实施例，对本发明做进一步的说明。
本发明实施例所用的实验方法如无特殊说明，均为常规方法。
本发明实施例所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
实施例1
原代细胞培养基由SFM培养基、胰岛素25μg/mL、链丝菌蛋白酶0.4g/L、亚硒酸钠13μg/mL、天门冬氨酸7.511.5mg、丝氨酸8mg/L、甘氨酸6mg/L、胆固醇25mg/L和纤粘连蛋白23μg/mL组成。
细胞传代培养基由DMEM培养基、纤粘连蛋白8μg/mL、胰岛素13ng/mL、丙酮酸钠180mg/L、葡萄糖2g/L、甘醇酸浓度为13μM组成。
全阵列细胞因子的制备方法，由以下步骤制得：
(1)将脐带组织剪至2mm3，将剪碎后的脐带组织加入原代培养基中，于37℃，5％CO2培养箱中进行培养，汇合度达到80％时，送检HBV、HIV、HCV、梅毒螺旋体、HTLV、CMV、EBV，检测符合质量要求的样本，得到原代细胞；
(2)细胞传代：将原代细胞，细胞密度为10000个细胞/cm2，放进细胞传代培养基中培养收集第5代细胞培养上清液，在37℃、5％CO2培养箱中进行培养，待细胞汇合度达到80％～90％时冻存细胞，并送检无菌、支原体、内毒素和细胞表型(CD73、CD90、CD105、CD45、CD34、CD19、CD14、HLA-DR等)，符合质量要求的细胞可用于细胞因子提取；
(3)细胞复融：从液氮罐中取出细胞，在37℃水浴中快速复融。细胞悬液用10倍体积的生理盐水洗涤一次后，离心，弃上清；
(4)细胞因子提取：将复融后的细胞采用注射用水重悬，将重悬细胞在23℃静置15min，再将重悬细胞浸入液氮中，得到冻结后的重悬细胞，冻结后的重悬细胞放入37℃水浴锅中复融，复融后的重悬细胞浸入液氮中，重复冻融4次，收集上清液，过滤，制得全阵列细胞因子，根据全阵列细胞因子体积加入0.1％的甘露醇进行冻干，在-30℃下预冻5h，调整冷冻干燥机温度-60℃，真空度为3Pa下冻干10h。
实施例2
原代细胞培养基由SFM培养基、胰岛素35μg/mL、链丝菌蛋白酶0.6g/L、亚硒酸钠17μg/mL、天门冬氨酸11.5mg、丝氨酸14mg/L、甘氨酸8mg/L、胆固醇45mg/L和纤粘连蛋白27μg/mL组成。
细胞传代培养基由DMEM培养基、纤粘连蛋白12μg/mL、胰岛素17ng/mL、丙酮酸钠200mg/L、葡萄糖4g/L、甘醇酸浓度为17μM组成。
全阵列细胞因子的制备方法，由以下步骤制得：
(1)将脐带组织剪至2mm3，将剪碎后的脐带组织加入原代培养基中，于37℃，5％CO2培养箱中进行培养，汇合度达到90％时，送检HBV、HIV、HCV、梅毒螺旋体、HTLV、CMV、EBV，检测符合质量要求的样本，得到原代细胞；
(2)将原代细胞，细胞密度为10000个细胞/cm2，放进细胞传代培养基中培养收集第5代细胞培养上清液，在37℃、5％CO2培养箱中进行培养，待细胞汇合度达到80％～90％时冻存细胞，并送检无菌、支原体、内毒素和细胞表型(CD73、CD90、CD105、CD45、CD34、CD19、CD14、HLA-DR等)，符合质量要求的细胞可用于细胞因子提取；
(3)细胞复融：从液氮罐中取出细胞，在37℃水浴中快速复融。细胞悬液用10倍体积的生理盐水洗涤一次后，离心，弃上清；
(4)细胞因子提取：将复融后的细胞采用注射用水重悬，将重悬细胞在23℃静置15min，再将重悬细胞浸入液氮中，得到冻结后的重悬细胞，冻结后的重悬细胞放入37℃水浴锅中复融，复融后的重悬细胞浸入液氮中，重复冻融4次，收集上清液，过滤，制得全阵列细胞因子，根据全阵列细胞因子体积加入0.1％的甘露醇进行冻干，在-30℃下预冻5h，调整冷冻干燥机温度-60℃，真空度为3Pa下冻干10h。
实施例3
原代细胞培养基由SFM培养基、胰岛素30μg/mL、链丝菌蛋白酶0.5g/L、亚硒酸钠15μg/mL、天门冬氨酸9mg、丝氨酸11mg/L、甘氨酸7mg/L、胆固醇35mg/L和纤粘连蛋白24μg/mL组成。
细胞传代培养基由DMEM培养基、纤粘连蛋白10μg/mL、胰岛素15ng/mL、丙酮酸钠190mg/L、葡萄糖3g/L、甘醇酸浓度为15μM组成。
全阵列细胞因子的制备方法，由以下步骤制得：
(1)将脐带组织剪至1-3mm3，将剪碎后的脐带组织加入原代培养基中，于37℃，5％CO2培养箱中进行培养，汇合度达到85％时，送检HBV、HIV、HCV、梅毒螺旋体、HTLV、CMV、EBV，检测符合质量要求的样本，得到原代细胞；
(2)细胞传代：将原代细胞，细胞密度为10000个细胞/cm2，放进细胞传代培养基中培养收集第5代细胞培养上清液，在37℃、5％CO2培养箱中进行培养，待细胞汇合度达到80％～90％时冻存细胞，并送检无菌、支原体、内毒素和细胞表型(CD73、CD90、CD105、CD45、CD34、CD19、CD14、HLA-DR等)，符合质量要求的细胞可用于细胞因子提取；
(3)细胞复融：从液氮罐中取出细胞，在37℃水浴中快速复融。细胞悬液用10倍体积的生理盐水洗涤一次后，离心，弃上清；
(4)细胞因子提取：将复融后的细胞采用注射用水重悬，将重悬细胞在23℃静置15min，再将重悬细胞浸入液氮中，得到冻结后的重悬细胞，冻结后的重悬细胞放入37℃水浴锅中复融，复融后的重悬细胞浸入液氮中，重复冻融4次，收集上清液，过滤，制得全阵列细胞因子，根据全阵列细胞因子体积加入0.1％的甘露醇进行冻干，在-30℃下预冻5h，调整冷冻干燥机温度-60℃，真空度为3Pa下冻干10h。
对比例1
在实施例3的基础上调整原代细胞培养基的组成，具体为：SFM培养基、胰岛素30μg/mL、戊酸雌二醇10ng/mL、天门冬氨酸9mg、丝氨酸11mg/L、甘氨酸7mg/L和纤粘连蛋白24μg/mL组成。
对比例2
在实施例3的基础上调整细胞传代培养基的组成，具体为：细胞传代培养基由DMEM培养基、胶原蛋白10μg/mL、胰岛素15ng/mL、维生素B2 0.3mg/L、丙酮酸钠190mg/L和葡萄糖3g/L组成。
对比例3
在实施例3的基础上调整细胞传代培养基的配比，具体为：细胞传代培养基由DMEM培养基、纤粘连蛋白16μg/mL、胰岛素23ng/mL、丙酮酸钠160mg/L、葡萄糖6g/L、甘醇酸浓度为15μM组成。
试验例1
采用实施例3制得干细胞全阵列因子作为雾化药物，将冻干后的干细胞全阵列因子5mg加30ml的注射用水溶解，采用映美HN300雾化器进行雾化，雾化时间为30min，试验地点为海南一龄医疗产业发展有限公司，时间为2022年12月，受试者共50位，其中有嗅觉障碍/味觉障碍的2人、活动后呼吸急促的3人、持续咳嗽45人、胸痛27人、呼吸21人和咽喉疼痛33人。在治疗期间，如果患者发烧，则需要服用退烧药，此外，患者未使用任何其它药物。每天每位患者接受一次雾化治疗，时间在30分钟左右，具体疗效见下表：
试验例2
采用ELISA试剂盒检测实施例3和对比例1-3制得的全阵列细胞因子中EGF、FGF、VEGF的含量。
试验结果表明，本发明中原代细胞培养基和细胞传代培养基能够促进细胞因子分泌增殖。
试验例3
将施例3和对比例1-3制得的全阵列细胞因子冻干前和冻干后细胞存活率测试，采用细胞荧光分析仪进行采集数据。
实验结果表明，本发明制得的干细胞全阵列因子和甘露醇复配冻干可以得到很好的保存效果，进一步表明本发明中原代细胞培养基和细胞传代培养基能够提高细胞的活力和稳定性。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (9)
1.一种具有改善呼吸系统感染作用的全阵列细胞因子，其特征在于：全阵列细胞因子包括FGF、G-CSF、GM-CSF、IFN-γ、IL-1β、IL-1ra、IL-2、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-12p70、IL-13、IL-15、IL-17A、IP-10、MCP-1/MCAF、MIP-1α、MIP-1β、PDGF-BB、RANTES、TNF-α、VEGF、EGF、HGF。
2.一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，包括以下步骤：
(1)脐带组织采用组织块贴壁法分离培养脐带间充质干细胞，得到原代细胞；
(2)细胞传代：原代细胞汇合度达到80％～90％时传代，收集第5代细胞培养上清液，冻干，得到传代细胞；
(3)细胞复融：将传代细胞水浴复融，细胞悬液用8-12倍体积的生理盐水洗涤一次后计数，离心，弃上清，得到复融后的细胞；
(4)细胞因子提取：将复融后的细胞采用注射用水重悬，将重悬细胞在23-27℃静置10-15min，再将重悬细胞浸入液氮中，得到冻结后的重悬细胞，冻结后的重悬细胞放入水浴锅中复融，复融后的重悬细胞浸入液氮中，重复冻融2-5次，收集上清液，过滤，制得全阵列细胞因子。
3.如权利要求2所述的一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，步骤(1)中，将脐带组织剪至1-3mm3，将剪碎后的脐带组织加入原代培养基中进行培养。
4.如权利要求3所述的一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，所述传代培养基包括基础培养基、胰岛素、胰高糖素、链丝菌蛋白酶、亚硒酸钠、天门冬氨酸、丝氨酸、甘氨酸、胆固醇和纤粘连蛋白。
5.如权利要求4所述的一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，所述基础培养基为SFM培养基，胰岛素25-35μg/mL、链丝菌蛋白酶0.4-0.6g/L、亚硒酸钠13-17μg/mL、天门冬氨酸7.5～11.5mg、丝氨酸8～14mg/L、甘氨酸6～8mg/L、胆固醇25-45mg/L和纤粘连蛋白23-27μg/mL。
6.如权利要求2所述的一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，步骤(2)中，细胞传代培养基包括基础培养基、纤粘连蛋白、胰岛素、丙酮酸钠、葡萄糖和甘醇酸。
7.如权利要求6所述的一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，所述基础培养基为DMEM培养基。
8.如权利要求7所述的一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，所述纤粘连蛋白8-12μg/mL、胰岛素13-17ng/mL、丙酮酸钠180-200mg/L、葡萄糖2-4g/L。
9.如权利要求6所述的一种具有改善呼吸系统感染作用的全阵列细胞因子的制备方法，其特征在于，所述甘醇酸浓度为13-17μM。
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