CN117924426A - 干细胞外泌体的制备技术及其在药品和化妆品中的应用 - Google Patents
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Abstract
本发明涉及干细胞外泌体的制备技术及其在药品和化妆品中的应用。本发明通过肽库筛选获得了具有较好的抗氧化应激损伤修复多肽，所述多肽经鉴定具有较好的抗氧化特性。该多肽与干细胞外泌体联合给药能够显著的提高皮肤光损伤的治疗效果，能够用于治疗皮肤损伤的药品或者化妆品，应用前景广阔。
Description
技术领域
本申请涉及生物领域，具体的涉及干细胞外泌体的制备技术及其在药品和化妆品中的应用。
背景技术
创面修复不仅存在愈合与否及愈合时间长短的问题,创面愈合后对机体功能和美观的影响也逐渐被人们关注。近年,随着分子生物学的迅猛发展、高新技术的应用和学科间的相互渗透,创面修复的基础研究已深入至细胞、分子及基因水平。
创伤大致分为炎症反应期、增殖期和重塑期三个阶段,一旦组织损伤,愈合的启动阶段即开始,创面愈合首先表现为局部炎症改变。炎症期中,由血小板释放出的血小板衍化生长因子(PDGF)、胰岛素样生长因子-1(IGF-1)、表皮细胞生长因子(EGF)、转化生长因子-β(TGF-β)等,作为炎症细胞的趋化剂而发挥重要作用。这些因子可刺激成纤维细胞、表皮细胞和血管内皮细胞向伤口移动。细胞增殖分化及肉芽组织形成阶段的主要特征是通过细胞的迁移、分化、增殖而实现缺损组织的修复,增生期中,成纤维细胞分泌IGF-1、bFGF、TGF-β、PDGF和角化细胞生长因子(KGF)；内皮细胞合成bFGF和PDGF；角化细胞合成TGF-β、TGF-α和角化细胞来源的自分泌因子(KAF)。这些生长因子刺激细胞增殖、细胞间基质蛋白合成和血管生成。其中转化生长因子-β(TGF-β)发挥了重要作用。创伤愈合通过伤口收缩、再生上皮覆盖或瘢痕形成而实现,组织重建过程涉及到许多生长因子和信号转导通路。表皮细胞生长因子(EGF)创面修复早期重要的参与细胞包括成纤维细跑、粒细胞、巨噬细胞,其中成纤维细胞浸润生长、增殖,不断的合成、分泌胶原,并通过胶原酶对胶原结构进行重塑,在一定程度上决定创面愈合的快慢与质量。
但是由于细胞因子种类多，成本高昂，通过添加细胞因子来治疗创面修复并不是较好的治疗方式。干细胞在组织修复与再生方面具有广阔的应用前景，已被广泛应用于转化医学领域，但目前干细胞发挥作用的机制还不十分清楚。近年来的研究表明，干细胞所发挥的组织修复与再生功能在很大程度上是由其旁分泌作用而实现的，而不是其在损伤部位的增殖和分化同时，干细胞移植始终存在一定的潜在风险，如移植细胞引起血管栓塞、干细胞遗传物质变异、促进肿瘤转移以及致瘤致畸等问题。而外泌体是其中一种重要的旁分泌因子，被越来越多的实验证明在干细胞修复损伤组织和组织再生方面起到关键作用。
近年来研究发现脐带间充质干细胞来源外泌体(HucMSC-Exo)内含的wnt4可以提高p-连环链蛋白的转位和活力，从而促进皮肤细胞的增殖与迁移和血管新生。HucMSC-Exo在皮肤缺损小鼠模型中可减少瘢痕形成和肌成纤维细胞的积累。这些功能主要是依赖于HucMSC-Exo包含的microRNAs,通过高通量RNA测序和功能分析，证明了HucMSC-Exo富含一组microRNAs(miR-21,miR-23a,miR-125b和miR-145),通过抑制TGF-P2/SMAD2信号通路抑制a-平滑肌肌动蛋白和股原过量沉积，从而抑制肌成纤维细胞的形成，进而阻止了瘢痕的形成。研究还发现脂肪间充质干细胞来源外泌体(ASCs-Exo)能够以剂量依赖性方式刺激成纤维细胞的增殖、迁移和股原蛋白合成，并促进细胞周期蛋白1、N-钙黏蛋白、I型股原、III型股原和增殖细胞核抗原的表达，从而促进皮肤伤口的愈合。进一步研究发现脂肪间充质干细胞来源的微囊泡(ASC-MVs)通过传递miR-31促进内皮细胞的迁移和血管生成。其中的一个抗血管生成基因HIF-1,被认定是miR-31在血管内皮细胞的革巴向基因。研究表明，ASCs-Exo能够传输miR-125a到内皮细胞，抑制血管生成抑制剂DLL4的表达，促进血管内皮尖端细胞的形成，调节内皮细胞血管生成作用。
在创面愈合和瘢痕形成过程中，Fb和肌成纤维细胞(mFb)是纤维化主要的效应细胞，参与胶原合成、分泌。ADSC外泌体对Fb不仅有同样的调控作用，还可以在损伤初期对Fb起到保护作用。本课题组的研究显示，ADSC外泌体可通过PI3K/Akt信号通路促进Fb增殖和迁移，增加胶原沉积，加速创面愈合，同时还可以减轻创面愈合后的瘢痕形成。通过应用ADSC条件培养基预处理Fb可以明显减轻辐照造成的细胞老化。ADSC外泌体可以增强鼓膜基质纤维Fb活性，进而加速鼓膜损伤患者的修复。研究显示，当ADSC外泌体中包含了肺腺癌转移相关转录物1以及其他可能刺激Fb迁移和血管生成的因子时，可以通过促进Fb迁移促进缺血创面的愈合。在对小鼠皮肤缺损模型的研究中发现，脂肪干细胞源性外泌体能抑制成纤维细胞向肌成纤维细胞分化，提高胶原蛋白/胶原蛋白I、基质金属蛋白酶/基质金属蛋白酶抑制剂、转化生长因子-3/转化生长因子-1的比值，从而减少瘢痕形成。研究发现间充质干细胞来源的外泌体内包含的一些miR如miR-1、miR-3A、miR-125B和miR-145,能阻断转化生长因子/细胞信号传导分子2通路，抑制肌成纤维细胞过度纤维化，从而减少瘢痕形成。此外，实验证明，脂肪干细胞来源外泌体在晚期可以抑制胶原的合成而减轻瘢痕。
但是目前，采用外泌体治疗皮肤损伤修复的研究还不够多，特别是与其他药物组合使用来治疗皮肤损伤的方法还不够多，有待于进一步的改进。
发明内容
本发明提供了一种抗氧化促进皮肤损伤修复的活性多肽。
所述的多肽是通过噬菌体随机12肽库针对人成纤维细胞抗氧化特性进行初步筛选得到了13个DPPH自由基清除活性较好的抗氧化特性较好的初选多肽，随后采用人永生化上皮角质形成细胞系HaCaT抗氧化应激损伤修复状况进行复筛，得到了抗氧化特性最好的多肽anti-O-P3，其氨基酸序列如SEQ ID NO：1所示。
本发明一方面，提供了一种用于提供抗氧化损伤治疗的药物组合物，其含有本发明的抗氧化特性多肽anti-O-P3。
进一步的，本发明还提供了一种用于治疗皮肤抗衰老抗氧化损伤的药物组合物，其含有本发明的抗氧化特性多肽anti-O-P3。
进一步的，本发明还提供干细胞外泌体用于治疗皮肤损伤。
具体的，还提供了一种用于治疗皮肤抗衰老抗氧化损伤的药物组合物，其含有本发明的抗氧化特性多肽anti-O-P3和干细胞外泌体。
进一步的，本发明还提供了抗氧化特性多肽anti-O-P3和干细胞外泌体在制备用于治疗皮肤抗衰老抗氧化损伤的药物组合物中的用途。
根据本发明的实施例，上述药物制剂除以前面所述的药物组合物作为活性成分外，还包括药学上可接受的载体。根据本发明的实施例，所述药学可接受的载体为选自药学上可接受的溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂、高分子骨架材料和成膜材料中的至少一种。由此可以使得所述药物组合物能够制剂成型，呈现临床用药物制剂适于给药的形式。
本发明所述的药物组合物的药物制剂为药学上可接受的各种剂型，选自为非缓控释剂型、缓控释剂型或注射剂。其中非缓控释剂型选自：片剂、胶囊剂、双层片剂、多层片剂、肠溶片、肠溶胶囊、滴丸剂、微丸剂、丸剂、分散片、颗粒剂、干混悬剂、泡腾片、散剂、口腔崩解片、咀嚼片、口服混悬剂、口服溶液剂、口服乳剂、含片、舌下片、酊剂、栓剂、软膏剂、气雾剂、喷雾剂、膜剂、乳剂、搽剂、凝胶剂或透皮帖剂；缓控释剂型选自：缓释片、缓释胶囊、控释片或控释胶囊；注射剂选自：小容量注射剂、无菌冻干粉针、无菌粉末分装或大容量注射剂。
进一步的，本发明的药物组合物中还含有合适的崩解剂。
适宜的崩解剂将是本领域技术人员已知的，非限制性的实例包括交联羧甲基纤维素钠、淀粉羟乙酸钠、交联聚乙烯吡咯烷酮、聚维酮、淀粉(例如玉米淀粉、预胶化淀粉)、低取代的羟丙基纤维素、海藻酸、海藻酸钠、三价磷酸钙、硫酸钙、羧甲基纤维素钙、微晶纤维素、粉状纤维素、二氧化硅胶体、多库酯钠、瓜尔胶、羟丙基纤维素、硅酸镁铝、甲基纤维素、聚克立林钾和聚乙烯吡咯烷酮。交联羧甲基纤维素钠是优选的。崩解剂可以单独使用或与其它物质组合。
本发明的药物组合物还包括填充剂。合适的填充剂可以选自微晶纤维素、优化微晶纤维素、粉状纤维素、糖类、糖衍生物、氨基酸、氨基酸盐、枸橼酸钠、磷酸氢二钠、葡甲胺、甘露醇、乳糖、山梨醇、聚乙二醇、碳酸氢钠、碳酸钙、磷酸钙、磷酸氢钙、表面活性剂、矫味剂、芳香剂、着色剂或其混合物。
本发明药物组合物还包括合适的润滑剂。合适的湿润剂或溶剂可以选自水、乙醇、聚乙二醇或乙醇水溶液；优选为水或乙醇水溶液；乙醇水溶液优选为30％～90％的乙醇水溶液；合适的矫味剂选自蔗糖、糖粉、三氯蔗糖、甜菊素、糖精钠、阿斯巴甜、乳糖或其混合物。
进一步的，本发明的干细胞外泌体是鼠源的。
具体的，将所述的干细胞进行培养后，合并培养基级分然后可以进行外泌体分离，特别是在4℃进行。条件培养基可以在约2℃、4℃、6℃、8℃、10℃、12℃、14℃、16℃、18℃、20℃、22℃、24℃或26℃的温度下离心。在一个实施方案中，条件培养基在约4℃的温度下离心。可以通过本领域已知的用于外泌体分离的方法进行外泌体的分离。优选地，如以上外泌体的产生，外泌体的分离也在封闭系统中进行。这可以通过使用泵和密封管来完成。分离可以包括离心步骤以去除大的碎片，接着过滤，和一个或多个超速离心步骤。分离方法可以进行多次，以处理所有合并的培养基级分，诸如3次。离心步骤可以包括以约500-2,000g、诸如约1,000g离心约5-25min,诸如约15min。条件培养基可以在约1,000g、2,000g、4,000g、6,000g、8,000g；10,0000g；12,000g、14,000g、16,000g或18,000g下离心。离心可以达诸如10-30分钟,12-28分钟,14-24分钟,或15-20分钟的时间。如本领域技术人员将理解，适当的可商购的实验室离心机例如THERMO-SCIENTIFICTM或COLE-PARMERTM用于进行该离心步骤。具体地，离心可以在封闭系统(诸如Cobe2991细胞处理器(Terumo))中进行。可以进行超过一次的低速离心以去除活细胞、死细胞和较大的细胞碎片。过滤步骤可以包括使用具有亚微米滤器的过滤袋，诸如0.1-0.3微米滤器，诸如0.2微米滤器，以去除碎片，诸如较大的微囊泡。上清液然后可以使用与管直接线连接的注射器转移至管(例如，聚碳酸酯管)。过滤可以重复超过一次。过滤可以通过一次或多次通过相同尺寸的滤器(例如0.2微米滤器)来进行。备选地，可以使用2个或更多个滤器进行过滤，使用相同或减小尺寸的滤器，例如一次或多次通过40-50微米滤器，一次或多次通过20-30微米滤器，一次或多次通过10-20微米滤器，一次或多次通过0.2-10微米滤器等。用于该步骤的适当滤器包括使用0.45和0.22微米滤器。超速离心可以以75,000至150,000g、诸如100,000至170,000g、诸如约100,000g进行约2-6小时,诸如1-3小时,诸如约4或5小时。任何可商购的超速离心机，例如THERMO-SCIENTIFICTM或BeckmanTM，可以用于进行该步骤。具体地，超速离心可以使用任何封闭系统的离心机进行，所述离心机诸如但不限于45Ti型转子(Beckman-Coulter)。该超速离心步骤可以任选地重复例如2次或更多次，以便增强结果。使用确立的技术从上清液中取出含有外泌体的沉淀，并且重悬于适当的生理溶液中。本领域技术人员将理解，来自任何离心或超速离心步骤的外泌体沉淀可以在离心步骤之间使用适当的生理溶液洗涤，所述生理溶液例如无菌PBS、无菌0.9％盐水或无菌含糖的0.9％盐水缓冲液。
在其他非限制性实施例中，所述外泌体和多肽的给药量一个剂量也可以包括每次给药约1微克/kg/体重、约5微克/kg/体重、约10微克/kg/体重、约50微克/kg/体重、约100微克/kg/体重、约200微克/kg/体重、约350微克/kg/体重、约500微克/kg/体重、约1毫克/kg/体重、约5毫克/kg/体重、约10毫克/kg/体重、约50毫克/kg/体重、约100毫克/kg/体重、约200毫克/kg/体重、约350毫克/kg/体重、约500毫克/kg/体重、至约1000mg/kg/体重或更多，和其中衍生的任何范围。在从本文列出的数字衍生的范围的非限制性实施例中，基于上述数字，可以施用约5mg/kg/体重至约100mg/kg/体重、约5微克/kg/体重至约500毫克/kg/体重的范围等等。
有益效果
本发明通过肽库筛选获得了具有较好的抗氧化应激损伤修复多肽，所述多肽经鉴定具有较好的抗氧化特性。该多肽与干细胞外泌体联合给药能够显著的提高皮肤光损伤的治疗效果，能够用于治疗皮肤损伤的药品或者化妆品，应用前景广阔。
附图说明
图1anti-O-P3多肽的抗氧化特性鉴定结果图
图2各组治疗后的残余创面百分比结果图
具体实施方式
下面将参照附图更详细地描述本发明的具体实施例。虽然附图中显示了本发明的具体实施例，然而应当理解，可以以各种形式实现本发明而不应被这里阐述的实施例所限制。相反，提供这些实施例是为了能够更透彻地理解本发明，并且能够将本发明的范围完整的传达给本领域的技术人员。
实施例1抗氧化应激损伤修复多肽的筛选
将人永生化上皮角质形成细胞系HaCaT用DMEM细胞培养基(含体积分数10％胎牛血清)在37℃、5％CO2环境下培养，每2d进行换液，使细胞密度达到1×106个。设置空白组、对照组(不加样品，加800μmol/LH2O2)和实验组(加入不同的修复肽，样品浓度为50μmol/L，加800μmol/L H2O2)。在96孔板中加入100μL细胞悬液，于37℃、5％CO2培养箱培养24h使其贴壁。24h后，弃旧培养基，按照多肽浓度上样，补齐DMEM使培养基的总体积为100μL。1h后，加入H2O2使H2O2浓度为800μmol/L。继续培养24h后，弃旧培养基，加入质量浓度为1mg/mL的MTT溶液，每个孔加100μL，4h后，弃MTT溶液，在96孔板中加入DMSO溶液，每孔100μL，摇床摇晃10min(避光操作)，使每孔中的液体呈蓝紫色透明状无沉淀，在540nm处测D值。根据D值，计算实验组与对照组比值，评价多肽对H2O2损伤的HaCaT细胞损伤的保护能力，结果如表1所示。
表1多肽对细胞相对活力的影响
| 组别 | 细胞相对活力(％) |
| 空白组 | 100 |
| 对照组 | 43.31±0.83 |
| anti-O-P1 | 59.37±0.96* |
| anti-O-P2 | 57.18±1.13* |
| anti-O-P3 | 95.44±2.57* |
| anti-O-P4 | 60.23±1.02* |
| anti-O-P5 | 65.82±1.24* |
| anti-O-P6 | 58.19±0.97* |
| anti-O-P7 | 73.87±1.17* |
| anti-O-P8 | 70.31±0.89* |
| anti-O-P9 | 81.34±1.28* |
| anti-O-P10 | 69.85±0.76* |
| anti-O-P11 | 63.48±0.84* |
| anti-O-P12 | 80.17±1.18* |
| anti-O-P13 | 73.26±0.76* |
从表1可以看出，初筛的13个多肽对H2O2诱导的氧化损伤均有保护作用，差异较对照组(*表示P<0.05)差异显著，其中anti-O-P3多肽对H2O2诱导的氧化损伤的保护作用最好，以该多肽进行后续的实验，其氨基酸序列为：RPFWISTACGKA。
实施例2anti-O-P3多肽的抗氧化特性鉴定
人永生化上皮角质形成细胞系HaCaT细胞中加入DMEM使细胞密度达到1×106个，采用不同的浓度anti-O-P3多肽(10μmol/L、50μmol/L、100μmol/L)处理细胞。在24孔板中加入200μL细胞悬液，于37℃、5％CO2培养箱培养24h使其贴壁。24h后，弃旧培养基，按照样品浓度梯度上样，补齐DMEM使培养基的总体积为200μL。1h后，加入适量H2O2，使H2O2浓度为800μmol/L。24h后，吸出旧培养基，用DMEM培养基震荡清洗3次，每次3min。清洗完成后，每孔加入荧光试剂DCFH-DA(10μmol/L)试剂100μL，震荡使其充分接触贴壁细胞，避光置于37℃、5％CO2培养箱孵育20min。然后弃荧光试剂，PBS清洗3次，每次4min。清洗完成后吸净所有的PBS，荧光倒置显微镜下观察以空白组的荧光染色结果为100，结果如图1所示。
从图1可以看出，相对于空白组(正常细胞，不添加H2O2处理)，对照组(采用H2O2处理)的荧光效果显著增强(P<0.05)，差异显著，说明H2O2作用于细胞后产生了较多的ROS。而加入不同浓度的多肽处理后，随着多肽浓度的增大，荧光强度逐渐减弱，说明细胞中的ROS逐渐减少。当样品浓度达到100μmol/L时细胞荧光强度与空白组接近，说明多肽可以在一定浓度内清除细胞氧化应激损伤产生的ROS，其清除ROS能力在一定范围随着多肽浓度增大而增强。
实施例3干细胞外泌体的制备
取3月龄SPF级雌性SD大鼠，无菌条件下取出大鼠双侧股骨和胫骨，剪开干骺端，抽取无血清DMEM低糖培养基反复冲洗骨髓腔4次，过滤，1200r/min离心5min，加入红细胞裂解液裂解5min，1000r/min离心5min，弃上清，洗涤2次后用8mL含体积分数为10％胎牛血清的DMEM低糖培养基重悬细胞，于37℃、体积分数为5％CO2培养箱静置培养3d，移除不贴壁的细胞；每48h换液或传代后，进行爬片处理，经过一抗、二抗孵育后，荧光显微镜下观察CD29、CD90以及CD45的阳性表达。免疫荧光结果显示：分离并培养的细胞CD29、CD90呈阳性表达，两者的阳性率均大于93％；而CD45呈阴性表达，说明分离制备得到了骨髓间充质干细胞。
选取第4代骨髓间充质干细胞，调整细胞浓度为1×108L-1，接种于10cm细胞培养皿，37℃、体积分数为5％CO2培养箱内培养24h后加入8mL含体积分数为10％血清的DMEM低糖完全培养基培养48h。细胞培养上清液以3000×g离心10min去除细胞碎片，2000×g离心10min以去除死细胞，4℃以10000×g离心60min，弃上清，用PBS均匀吹打，4℃以12000×g离心2min，保留上清液，该上清液中富含外泌体颗粒。将收获的外泌体颗粒粗品转入ExosomePurification Filter(EPF柱)上室中，于4℃以3000×g离心10min，离心后收集纯化后的外泌体颗粒。将上述外泌体纯化通风处理后，采用漂浮法用醋酸双氧铀负染，通过透射电镜观察外泌体形态为囊状球形，采用纳米颗粒跟踪分析仪检测外泌体粒径分布范围主要在90-130nm范围。按BCA试剂盒步骤测定蛋白浓度为2.31mg/mL。
实施例4多肽和外泌体功效验证
雌性成年大鼠，购买后自由采食7d。以10％水合氯醛300mg/kg对大鼠进行腹腔麻醉，用刀剔去大鼠背部部分毛发。深麻醉起效后，绷紧大鼠背部局部皮肤，将小鼠麻醉后俯卧在手术台上，用电剪刀和脱毛蜡依次剃除背部区域的毛发后，用活检穿孔器在每只小鼠背部打出直径14mm的皮肤全层圆形伤口。损伤模型建立后，用无菌纱布清理创口处血污，所有小鼠随机分组，每组5只，分别为空白模型组(50μL PBS)、阳性对照组(云南白药粉30μg加入50μL PBS)、多肽组(anti-O-P3多肽30μg加入50μL PBS)、外泌体组(100μg外泌体加入50μL PBS)和外泌体和多肽联合组(anti-O-P3多肽30μg和100μg外泌体混合后PBS定容到50μL)。所有药物每日1次局部涂抹于伤口部位。术后第9天观察伤口部位并拍照，使用Image-ProPlus 6.0软件进行残余创面百分比分析，残余创面百分比＝第9天创伤面积/第0天创伤面积×100％。
从图2可以看出，本发明的多肽和外泌体均可以有效的促进创面伤口的愈合，与空白模型组相比，差异显著；特别是外泌体和多肽联合使用后，能够极显著的促进创面的愈合，在第9天参与创面百分比只有(14.9±0.87)％，比阳性对照组的(29.4±1.8)％残余创面显著降低，说明具有更好的治疗效果。
尽管以上结合附图对本发明的实施方案进行了描述，但本发明并不局限于上述的具体实施方案和应用领域，上述的具体实施方案仅仅是示意性的、指导性的，而不是限制性的。本领域的普通技术人员在本说明书的启示下和在不脱离本发明权利要求所保护的范围的情况下，还可以做出很多种的形式，这些均属于本发明保护之列。
Claims (6)
1.一种抗氧化促进皮肤损伤修复的活性多肽，其命名为anti-O-P3，特征在于其氨基酸序列如SEQ ID NO：1所示。
2.一种用于皮肤抗氧化促进伤口损伤修复的药物组合物，其特征在于含有权利要求1所述的抗氧化特性多肽anti-O-P3。
3.一种用于治疗皮肤抗氧化促进伤口损伤修复的药物组合物，其特征在于由权利要求1所述的抗氧化特性多肽anti-O-P3和骨髓间充质干细胞外泌体组成。
4.权利要求1所述的抗氧化特性多肽anti-O-P3和骨髓间充质干细胞外泌体在制备用于治疗皮肤抗氧化促进伤口损伤修复的药物组合物中的用途。
5.一种用于皮肤抗氧化的化妆品，其特征在于含有权利要求1中所述的anti-O-P3多肽。
6.权利要求1所述的抗氧化特性多肽anti-O-P3和骨髓间充质干细胞外泌体在制备用于治疗皮肤抗氧化的化妆品中的用途。
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| CN114432427A (zh) * | 2022-03-07 | 2022-05-06 | 北京岳淘生物科技有限公司 | 抗衰老活性肽与骨髓间充质干细胞在制备抗衰老的药物或者美容产品中的用途 |
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| CN114432427A (zh) * | 2022-03-07 | 2022-05-06 | 北京岳淘生物科技有限公司 | 抗衰老活性肽与骨髓间充质干细胞在制备抗衰老的药物或者美容产品中的用途 |
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