CN117157054A - 包含干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或治疗伤口用组合物及其用途 - Google Patents
包含干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或治疗伤口用组合物及其用途 Download PDFInfo
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Abstract
本发明涉及一种包含皮肤再生、美白或者抗氧化功能提高的干细胞来源的外泌体作为有效成分的组合物。更具体地,本发明涉及一种包含尿源干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或治疗伤口用化妆品组合物或者药物组合物。
Description
技术领域
本发明涉及一种包含皮肤再生、美白或抗氧化功能提高的干细胞来源的外泌体作为有效成分的组合物。更具体地,本发明涉及一种作为有效成分包含尿源干细胞来源的外泌体的皮肤再生、美白、抗氧化或治疗伤口用化妆品组合物或药物组合物。
背景技术
尿源干细胞是能够通过简单分离过程从人体尿液中获得干细胞的新干细胞源,与其他间叶干细胞相比,完全不会诱发患者疼痛和后遗症,且可以多次获得干细胞,因此与现有的细胞源相比能够获得更多初期培养所需的干细胞数量。另外,尿源干细胞增殖率高,短期内能够获得较多细胞数,因此商用化可能性高,HLA-DR的表达低,可以用作体内移植时不会诱发免疫反应的自体细胞治疗剂,因此具有非常容易接近临床的优点。此外,尿源干细胞在适宜的培养环境下分泌包括各种生长因子在内的细胞因子等,其治疗潜力得到了认可。
最近有研究报道,细胞分泌的分泌物(Secretome)中包含调节细胞活动的生物活性因子。外泌体(Exosome)是从细胞中分泌的30~150nm大小的纳米内质网[1,2]。已知外泌体包括mRNA、miRNA等遗传物质和细胞因子等蛋白质运输物质,根据细胞类型不同,根据分泌的环境进行不同的调节。外泌体作为细胞间信号传输介质,通过其传输的各种细胞信号调节靶细胞的激活、生长、迁移、分化、去分化、死亡、坏死等。另外,外泌体根据细胞来源的性质和状态包含特异性遗传物质和生物活性因子。尤其是干细胞外泌体根据干细胞的特性,含有与干细胞的细胞增殖、分化、再生相关的基因、蛋白质、生长因子等,在组织再生中起着重要作用[3,4,5]。
最近,随着老龄化人口的增加和多种皮肤美容技术的增加,消费者对改善皮肤老化的需求日益提高。另外,随着对干细胞外泌体的研究活跃进行,开发安全、功效优秀的功能性外泌体化妆品是化妆品行业主要关注的课题。干细胞外泌体能够用作改善皮肤老化现象的抗老化化妆品原料,对此的研究正活跃进行。
因此,本发明人等通过有效地分离和纯化尿源干细胞增殖时分泌的外泌体,并证明尿源干细胞外泌体的伤口再生、改善皱纹、皮肤美白等功效,开发对人体无副作用、功效优秀的新功能性化妆品。
现有文件
非专利文献1:S,E.L.A.,Mager,I.,Breakefield,X.O.&Wood,M.J.Extracellularvesicles:biology and emerging therapeutic opportunities.Nature reviews.Drugdiscovery 2013.12,347-357.
非专利文献2:Sahoo,S.et al.Exosomes from human CD34(+)stem cellsmediate their proangiogenic paracrine activity.Circulation research,2011.109,724-728.
非专利文献3:Schorey,J.S.&Bhatnagar,S.Exosome function:from tumorimmunology to pathogen biology.Traffic,2008,9,871-881.
非专利文献4:Thery,C.,Zitvogel,L.&Amigorena,S.Exosomes:composition,biogenesis and function.Nature reviews.Immunology,2002.2,569-579.
非专利文献5:Vishnubhatla,I.,Corteling,R.,Stevanato,L.,Hicks,C.&Sinden,J.The Development of Stem Cell-derived Exosomes as a Cell-freeRegenerative Medicine.Journal of Circulating Biomarkers,2014.1.
发明内容
技术课题
本发明人等在韩国专利申请第10-2019-0139702号中公开了用于培养尿源干细胞的培养基组合物以及利用其培养尿源干细胞的方法。本发明人等在持续进行对所述尿源干细胞的研究的过程中,发现尿源干细胞中分泌的外泌体具有伤口再生、改善皱纹、皮肤美白等改善皮肤老化功效,并完成了本发明。
解决课题方法
本发明的目的在于提供一种包含尿源干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或治疗伤口用化妆品组合物。
本发明的另一目的在于提供一种包含尿源干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或治疗伤口用药物组合物。
本发明又一目的在于提供一种包含尿源干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或治疗伤口用食品组合物。
本发明又一目的在于提供一种用于皮肤再生、美白、抗氧化或治疗伤口的尿源干细胞来源的外泌体的制备方法。
本说明书中使用的术语“干细胞”是指能够分化成个体的所有组织细胞的具有多能性(pluripotent)或全能性(totipotent)的自我再生能力(self-renewal)的细胞,包括胚胎干细胞、诱导多功能干细胞以及成体干细胞。
本说明书中使用的术语干细胞的“增殖”是指干细胞不分化成具体的细胞,而是维持干细胞的特性直接进行细胞***,从而细胞总数增加。
本说明书中使用的术语“培养液”是指包含在体外(in vitro)维持细胞生长和存活所需的营养物质的组合物。
本说明书中使用的术语“细胞治疗剂”是指由个体通过分离、培养及特殊操作制备的细胞和组织,用于治疗、诊断和预防目的的药品,是指为了恢复细胞或组织的功能,通过体外增殖筛选自体、同种或异种细胞或通过其他方式改变细胞的生物学特性等的一系列行为,将这些细胞用于治疗、诊断和预防疾病的药品。
本说明书中使用的术语“外泌体”是指由细胞分泌,包括mRNA、miRNA等遗传物质和细胞因子等蛋白质运载物质的30~150nm大小的纳米内质网。
发明效果
本发明的包含尿源干细胞来源的外泌体作为有效成分的组合物无细胞毒性,且安全(实施例3),具有优秀的细胞增殖率(实施例4),具有治疗伤口(实施例5)、改善皮肤皱纹(实施例6)以及皮肤美白(实施例8)的效果。因此,本发明的包含尿源干细胞来源的外泌体作为有效成分的组合物有望作为皮肤再生、美白、抗氧化或治疗伤口用化妆品组合物、药物组合物以及食品组合物使用。
附图说明
图1表示根据实施例1通过TFF方法分离的外泌体内蛋白质的浓度。
图2表示根据实施例1分离的外泌体的颗粒大小。
图3表示根据实施例1分离的外泌体内存在的标记物。
图4表示根据实施例1分离的外泌体的细胞毒性。
图5表示根据实施例1分离的外泌体的细胞增殖率。
图6表示根据实施例1分离的外泌体对人皮肤成纤维细胞以及人角质形成细胞的迁移的影响效果。
图7表示根据实施例1分离的外泌体的改善皱纹效果。
图8表示根据实施例1分离的外泌体的美白效果。
具体实施方式
根据第一实施方案,本发明提供一种作为有效成分包含尿源干细胞来源的外泌体的皮肤再生、美白、抗氧化或治疗伤口用化妆品组合物。
本发明的化妆品组合物中,所述外泌体能够在培养尿源干细胞的过程中分离和纯化,用于培养所述尿源干细胞的培养基组合物如本发明人等的韩国专利申请第10-2019-0139702号所记载。例如,用于培养所述尿源干细胞的培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基(Dulbecco's Modified Eagle's Medium,DMEM)和哈姆F-12(Ham's F12)的基础培养基、2.5%以下的牛胎血清以及添加剂,所述添加剂为选自由牛血清白蛋白、脂质混合物(chemically defined lipids)、成纤维细胞成长因子23(fibroblast growth factor 23,FGF23)、三碘甲状腺原氨酸(triiodothyronine,T3)以及骨化二醇(calcifediol)组成的组中的一种以上。优选地,用于培养所述尿源干细胞的培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基(DMEM)和哈姆F-12(Ham’sF12)的基础培养基、2.5%以下的牛胎血清、牛血清白蛋白、脂质混合物(chemicallydefined lipids)、成纤维细胞成长因子23(fibroblast growth factor 23,FGF23)、三碘甲状腺原氨酸(triiodothyronine,T3)以及骨化二醇(calcifediol),或者以上成分组成。用于从所述尿源干细胞中提取外泌体的培养基组合物是无血清、无抗生素培养基组合物。所述无血清、无抗生素培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基(DMEM)和哈姆F-12(Ham’s F12)的基础培养基、成纤维细胞生长因子2(FGF2)、皮质醇、三碘甲状腺原氨酸(triiodothyronine,T3)、骨化三醇、胰岛素-转铁蛋白-硒-乙醇胺、L-抗坏血酸-2-磷酸酯以及视黄酸,或者以上成分组成。
本发明的化妆品组合物中,所述尿源干细胞来源于自体、异体或者异种。
本发明的化妆品组合物中,所述伤口包括割伤(cut)、切口(incisions)(例如,手术切口)、擦伤(abrasions)、撕裂伤或者撕裂(lacerations)、骨折(fracture)、挫伤(contusions)、烧伤(burns)或者截肢(amputations)。
本发明的化妆品组合物中,所述化妆品组合物除所述有效成分外,包括通常用于化妆品组合物的成分,包括例如脂肪物质、有机溶剂、溶解剂、浓缩剂和凝胶化剂、软化剂、抗氧化剂、悬浮剂、稳定剂、发泡剂(foaming agent)、芳香剂、表面活性剂、水、离子型或非离子型乳化液、填充剂、金属离子封锁剂和螯合剂、保存剂、维生素、阻隔剂、润湿剂、必需油类、染料、颜料、亲水性或亲油性活性剂、脂质囊等通常助剂以及载体。
本发明的化妆品组合物中,所述化妆品组合物在本领域中可制备成通常制备的任何剂型,可制备成例如溶液、悬浮液、乳浊液、膏状物、凝胶、霜、乳液、粉末、油、粉末粉底液、乳浊液粉底液、蜡粉底液、喷雾等,但不限于此。更详细而言,可制备成爽肤水、柔肤水、护肤水、收敛剂、乳液、润肤乳、保湿乳、营养乳、按摩霜、营养霜、眼霜、保湿霜、护手霜、精华液、营养精华液、面膜、洗面奶、卸妆水、卸妆乳、洁面霜、身体乳、沐浴露、皂以及粉末的化妆品剂型。
所述化妆品组合物的剂型为膏状物、霜或者凝胶的情况下,作为载体成分可使用动物油、植物油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅、膨润土、二氧化硅、滑石或氧化锌等。
所述化妆品组合物的剂型为粉末或喷雾的情况下,作为载体成分可使用乳糖、滑石、二氧化硅、氢氧化铝、硅酸钙或聚酰胺粉末,尤其是在喷雾的情况下,可以进一步包括氟氯烃(chlorofluoro hydrocarbon)、丙烷/丁烷或二甲醚等推进剂。
所述化妆品组合物的剂型为溶液或者乳浊液的情况下,作为载体成分,使用溶剂、溶解剂或者乳浊剂,包括例如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇油、甘油脂肪族酯、聚乙二醇或山梨糖醇的脂肪酸酯。
所述化妆品组合物的剂型为悬浮液的情况下,作为载体成分,可使用水、乙醇或者丙二醇等液体稀释剂,乙氧基化异硬脂醇、聚氧乙烯山梨醇酯、聚氧乙烯山梨糖醇酯等悬浮剂、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨润土、琼脂或黄蓍胶等。
根据第二实施方案,本发明还提供一种包含尿源干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或治疗伤口用药物组合物。
本发明的药物组合物中,所述外泌体能够在培养尿源干细胞的过程中分离和纯化,用于培养所述尿源干细胞的培养基组合物如本发明人等的韩国专利申请第10-2019-0139702号所记载。例如,用于培养所述尿源干细胞的培养基组合物的特征为,包括以3:1的比例包含杜尔贝科改良伊格尔培养基(Dulbecco's Modified Eagle's Medium,DMEM)和哈姆F-12(Ham's F12)的基础培养基、2.5%以下的牛胎血清以及添加剂,所述添加剂为选自由牛血清白蛋白、脂质混合物(chemically defined lipids)、成纤维细胞成长因子23(fibroblast growth factor 23,FGF23)、三碘甲状腺原氨酸(triiodothyronine,T3)以及骨化二醇(calcifediol)组成的组中的一种以上。优选地,用于培养所述尿源干细胞的培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基(DMEM)和哈姆F-12(Ham’sF12)的基础培养基、2.5%以下的牛胎血清、牛血清白蛋白、脂质混合物(chemicallydefined lipids)、成纤维细胞成长因子(fibroblast growth factor 23,FGF23)、三碘甲状腺原氨酸(triiodothyronine,T3)以及骨化二醇(calcifediol),或者以上成分组成。
本发明的药物组合物中,所述尿源干细胞来源于自体、异体或者异种。
本发明的药物组合物中,所述伤口包括割伤(cut)、切口(incisions)(例如,手术切口)、擦伤(abrasions)、撕裂伤或者撕裂(lacerations)、骨折(fracture)、挫伤(contusions)、烧伤(burns)或者截肢(amputations)。
本发明的药物组合物中,所述药物组合物可包括药剂学上可接受的稀释剂或者载体。所述稀释剂可以是乳糖、玉米淀粉、大豆油、微晶纤维素或者甘露醇,润滑剂可以是硬脂酸镁、滑石、或者其组合。所述载体可以是赋形剂、崩解剂、结合剂、润滑剂或其组合。所述赋形剂可以是微晶纤维素、乳糖、低取代度羟基纤维素或其组合。所述崩解剂可以是羧甲基纤维素钙、羟基乙酸淀粉钠、无水磷酸氢钙或其组合。所述结合剂可以是聚乙烯吡咯烷酮、低取代度羟丙基纤维素、羟丙基纤维素或其组合。所述润滑剂可以是硬脂酸镁、二氧化硅、滑石或其组合。
本发明的药物组合物中,所述药物组合物可以制备成非口服给药剂型。非口服给药剂型可以是注射剂或者皮肤外用剂。皮肤外用剂可以是霜、凝胶、软膏、皮肤乳化剂、皮肤悬浮液、透皮贴剂、面膜、含药物绷带、乳液、或者其组合。所述皮肤外用剂可根据通常用于化妆品或药品等皮肤外用剂的成分,例如水性成分、油性成分、粉末成分、醇类、保湿剂、增稠剂、紫外线吸收剂、美白剂、防腐剂、抗氧化剂、表面活性剂、香料、色素、各种皮肤营养剂、或其组合和需要适当地配制。所述皮肤外用剂也可以适当地配制乙二胺四乙酸二钠、乙二胺四乙酸三钠、柠檬酸钠、聚磷酸钠、偏磷酸钠、葡萄糖酸等螯合剂、咖啡因、单宁、维拉帕米、甘草提取物、光甘草定、木瓜的果实的热水提取物、各种生药、生育酚乙酸酯、甘草酸、氨甲环酸及其衍生物或其盐等药剂、维生素C、抗坏血酸磷酸镁、抗坏血酸葡萄糖苷、熊果苷、曲酸、葡萄糖、果糖、海藻糖等糖类。
根据第三实施方案,本发明还提供一种包含尿源干细胞来源的外泌体作为有效成分的皮肤再生、美白、抗氧化或者伤口的预防或缓解用食品组合物。
本发明的食品组合物中,所述外泌体能够在培养尿源干细胞的过程中分离和纯化,用于培养所述尿源干细胞的培养基组合物如本发明人等的韩国专利申请第10-2019-0139702号所记载。例如,用于培养所述尿源干细胞的培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基(DMEM)和哈姆F-12(Ham’s F12)的基础培养基、2.5%以下的牛胎血清以及添加剂,所述添加剂选自由牛血清白蛋白、脂质混合物(chemically definedlipids)、成纤维细胞成长因子23(fibroblast growth factor 23,FGF23)、三碘甲状腺原氨酸(triiodothyronine,T3)以及骨化二醇(calcifediol)组成的组中的一种以上。优选地,用于培养所述尿源干细胞的培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基(DMEM)和哈姆F-12(Ham’s F12)的基础培养基、2.5%以下的牛胎血清、牛血清白蛋白、脂质混合物(chemically defined lipids)、成纤维细胞成长因子23(fibroblastgrowth factor 23,FGF23)、三碘甲状腺原氨酸(triiodothyronine,T3)以及骨化二醇(calcifediol),或者以上成分组成。
本发明的食品组合物中,所述尿源干细胞来源于自体、异体或者异种。
本发明的食品组合物中,所述伤口包括割伤(cut)、切口(incisions)(例如,手术切口)、擦伤(abrasions)、撕裂伤或者撕裂(lacerations)、骨折(fracture)、挫伤(contusions)、烧伤(burns)或者截肢(amputations)。
本发明的食品组合物除所述有效成分外,还可包括甜味剂、风味剂、生理活性成分、矿物质等。
本发明的食品组合物根据需要可包括保存剂、乳化剂、酸味剂、增稠剂等。优选这些保存剂、乳化剂等以可实现其添加用途的极微量添加使用。极微量是指从数值上表示,以食品组合物的总重量为基准的0.0005重量%~约0.5重量%的范围。
根据第四实施方案,本发明提供一种用于皮肤再生、美白、抗氧化或治疗伤口的尿源干细胞来源的外泌体的制备方法,所述方法包括:
在包括以3:1的比例包含杜尔贝科改良伊格尔培养基(DMEM)和哈姆F-12(Ham’sF12)的基础培养基、2.5%以下的牛胎血清以及添加剂的培养基组合物中培养尿源干细胞的步骤;以及
在无血清、无抗生素培养基组合物中培养所培养的所述尿源干细胞并提取外泌体的步骤。
本发明的方法的特征为,所述添加剂包括牛血清白蛋白、脂质混合物(chemicallydefined lipids)、成纤维细胞成长因子23(fibroblast growth factor 23,FGF23)、三碘甲状腺原氨酸(triiodothyronine,T3)以及骨化二醇(calcifediol),或者以上成分组成。
本发明的方法中,所述无血清和无抗生素培养液包括以3:1的比例包含杜尔贝科改良伊格尔培养基(DMEM)和哈姆F-12(Ham’s F12)的基础培养基、成纤维细胞生长因子2(FGF2)、皮质醇、三碘甲状腺原氨酸(triiodothyronine,T3)、骨化三醇、胰岛素-转铁蛋白-硒-乙醇胺、L-抗坏血酸-2-磷酸酯以及视黄酸,或者以上成分组成。
以下,参照实施例和试验例,对本发明进行更详细的说明。但是,这些实施例和试验例用于例示本发明,本发明并非由这些实施例和试验例所限定。
<实施例>
实施例1.由人体尿源干细胞提取外泌体
将人体尿源干细胞传代(passage)培养至2至7代之后,更换为用于提取外泌体的无血清、无抗生素培养基后提取外泌体。具体地,本发明人等通过韩国专利申请第10-2019-0139702号的用于培养尿源干细胞的培养基组合物专利中公开的用于培养尿源干细胞的培养基组合物(参照以下的表1和表2),对人体尿源干细胞进行传代培养2代至7代后,更换为用于提取外泌体的无血清、无抗生素培养基(参照以下的表3),并培养24小时至96小时。
[表1]
[表2]
脂质混合物 | 浓度 |
花生四烯酸 | 2-20ng/ml |
胆固醇 | 220-2200ng/ml |
DL-α-生育酚乙酸酯 | 70-700ng/ml |
亚油酸 | 10-100ng/ml |
肉豆蔻酸 | 10-100ng/ml |
油酸 | 10-100ng/ml |
棕榈酸 | 10-100ng/ml |
棕榈油酸 | 10-100ng/ml |
嵌段式聚醚F-68(Pluronic F-68) | 90-900μg/ml |
硬脂酸 | 10-100ng/ml |
吐温80 | 2.2-22μg/ml |
[表3]
之后,回收细胞培养上清液,以300xg至500xg离心分离5分钟至15分钟以去除细胞,然后以12000xg至20000xg高速离心分离30分钟至60分钟以去除细胞残留物。之后,对于去除了细胞和细胞残留物的培养液,使用0.22μm过滤器进行过滤、或者使用具有500kDa至1000kDa的MWCO的TFF过滤器进行过滤以获得其过滤物,从而去除100nm至300nm以上大小的物质。之后,为了分离外泌体,使用具有30kDa至100kDa的MWCO的TFF过滤器进行过滤以获得其浓缩物,从而去除10nm至30nm以下大小的物质。进行所述过滤步骤,直到浓缩物体积浓缩至1/50至1/100体积。使用磷酸盐缓冲液(PBS)清洗所浓缩的外泌体。此时,以浓缩物体积的10倍至20倍体积添加PBS,并使用TFF过滤器进行浓缩。所述清洗过程进行了1次至10次。使用通过所述过程分离和纯化的外泌体来制备化妆品组合物,并用于以下试验。为了比较人体尿源干细胞外泌体的功效,作为对照组,从人体脂肪源干细胞中提取外泌体,通过与上述方法相同的方法提取外泌体。
实施例2.分离的外泌体的特性分析(BCA定量、NTA、Exo-check)
利用BCA显色法(赛默飞世尔科技,ThermoFisher Scientific)测定从所述实施例1的人体尿源干细胞中提取的外泌体(UD-exo)和作为对照组从脂肪源干细胞中提取的外泌体(AD-exo)的蛋白质的量。通过TFF方法分离、浓缩外泌体,采用蛋白质定量法测定蛋白质、脂质、核酸、小分子化合物等被去除的程度。其结果显示,通过实施例1的TFF方法非常有效地去除培养液中存在的蛋白质(图1)。
对于通过实施例1的方法分离的外泌体的颗粒大小,使用纳米颗粒跟踪分析(nanoparticle tracking analysis,NTA)重复5次测定。其结果显示,分离的外泌体大小分布均匀(图2)。
另外,对通过实施例1的方法分离的外泌体,使用Exo-check(***生物学,systembioscience)试剂盒进行外泌体标记物分析。其结果显示,CD63、CD81和EpCAM标记物存在于所分离的外泌体中(图3)。
实施例3.基于外泌体处理的细胞毒性测定
为了评估通过所述实施例1的分离方法获得的外泌体的毒性,对人皮肤成纤维细胞和人角质形成细胞以不同浓度处理外泌体并确认细胞毒性。将人皮肤成纤维细胞和人角质形成细胞悬浮在含有10%FBS的DMEM中,然后以具有80%至90%的密集度的方式进行分注,并在37℃、5%CO2培养箱中培养24小时。24小时后,去除培养液,将不含FBS的DMEM分注之后,分别以不同浓度处理从实施例1准备的人体尿源干细胞中提取的外泌体和作为对照组从人体脂肪源干细胞提取的外泌体,培养24小时至48小时,并评估细胞存活率。细胞存活率采用CCK-8(细胞计数试剂盒-8,cat#CK04-11)、MTT(abcam,cat#ab211091)和酶标仪进行测定。
其结果显示,以未经外泌体处理的DMEM中培养相同时间的细胞组为基准,在试验的浓度范围内未出现从人体尿源干细胞中提取的外泌体和从人体脂肪源干细胞中提取的外泌体引起的细胞毒性(图4)。
实施例4.基于外泌体处理的细胞增殖率测定
为了评估通过所述实施例1的分离方法获得的外泌体对人皮肤成纤维细胞和人角质形成细胞增殖率,对人皮肤成纤维细胞和人角质形成细胞进行不同浓度的外泌体处理,并确认细胞的增殖率。将人皮肤成纤维细胞和人角质形成细胞悬浮在含有10%FBS的DMEM中,然后以具有80%至90%的密集度的方式进行分注,并在37℃、5%CO2培养箱中培养24小时。24小时后,去除培养液,将不含FBS的DMEM分注之后,分别以不同浓度处理从实施例1准备的人体尿源干细胞中提取的外泌体和作为对照组从人体脂肪源干细胞提取的外泌体,培养48至72小时后评估不同外泌体浓度的细胞增殖率。细胞增殖率采用台盼蓝(trypanblue)的细胞计数(Cell counting)、CCK-8(细胞计数试剂盒-8,cat#CK04-11)、MTT(abcam,cat#ab211091)和酶标仪进行测定。
其结果显示,以未经外泌体处理的DMEM中培养相同时间的细胞组为基准,试验的外泌体的整体浓度下,从人体尿源干细胞中提取的外泌体的细胞增殖率比从人体脂肪源干细胞中提取的外泌体更优秀(图5)。
实施例5.利用从人体尿源干细胞中提取的外泌体的人皮肤成纤维细胞和人角质
形成细胞的迁移效果
为了了解从人体尿源干细胞中提取的外泌体(UD-exo)对人皮肤成纤维细胞和人角质形成细胞迁移的影响,使用了分别包含从人体尿源干细胞培养基中提取的外泌体和从人体脂肪源干细胞中提取的外泌体(AD-exo)的培养基组合物。所述培养基组合物中,UD-exo是以250μg/mL的浓度添加到DMEM无血清培养基中来使用,AD-exo是以250μg/mL的浓度添加到DMEM无血清培养基中来使用。作为阴性对照组,使用DMEM无血清培养基。人皮肤成纤维细胞和人角质形成细胞分别以2×105个细胞/孔分注至设置于24孔板的划痕试验(scratch assay)用框架内,在培养基(含有10%胎牛血清、1%青霉素/链霉素的DMEM)中培养24小时。培养后,小心地去除所设置的框架以制作一定间隔的伤口(wound),用含有外泌体的所述培养基组合物处理各细胞。在用含外泌体的培养基处理各细胞后0、6、12和18小时后拍照,并通过Image J对细胞的迁移程度进行数值化。
其结果显示,经过12小时开始,用含UD-exo的培养基处理的细胞(88.12%)比阴性对照组(26.44%)和用AD-exo(50.66%)处理的细胞迁移(migration)程度更高,经过18小时后与含AD-exo的培养基相比,在含UD-exo的培养基中迁移速度更快,成纤维细胞的迁移效果更优秀。在人角质形成细胞中,经含UD-exo的培养基处理的细胞(80.75%)也在经过12小时后开始迁移(migration)程度高于阴性对照组(36.53%)和经AD-exo(46.51%)处理的细胞(图6)。由此证明,从人体尿源干细胞中提取的外泌体比从人体脂肪源干细胞中提取的外泌体有更好的伤口恢复效果。
实施例6.从人体尿源干细胞中提取的外泌体的改善皱纹效果
为了了解从人体尿源干细胞中提取的外泌体对人皮肤成纤维细胞的胶原合成的影响,使用了分别包含从尿源干细胞培养基中提取的外泌体(UD-exo)和从脂肪源干细胞培养基中提取的外泌体(AD-exo)的培养基组合物。含UD-exo的培养基组合物通过在DMEM无血清培养基中添加250μg/mL浓度的UD-exo来使用,含AD-exo的培养基组合物通过在DMEM无血清培养基中添加250μg/mL浓度的AD-exo来使用,作为阴性对照组,使用DMEM无血清培养基。人皮肤成纤维细胞分别以3×105个/孔分注至6孔板中,在培养基(含有10%胎牛血清、1%青霉素/链霉素的DMEM)中培养24小时后,确认细胞是否粘附良好,然后用磷酸盐缓冲盐水清洗细胞,用含外泌体的所述培养基组合物处理各细胞。外泌体处理48小时后,为了确认胶原基因表达水平,分别回收各孔的人皮肤成纤维细胞和培养液,皮肤成纤维细胞是以25℃、2000rpm离心分离5分钟来获得,培养液是以25℃、3000rpm离心分离10分钟来获得。从回收的皮肤成纤维细胞获得的总RNA制备cDNA,然后使用以下的表4所示的引物进行实时PCR,测定胶原基因的mRNA变化量,回收的培养液是在离心分离后取所获得的上清液而用于水溶性胶原蛋白(soluble collagen)的提取和定量。作为用于胶原基因定量的标准基因,使用GAPDH基因。
[表4]
其结果可确认,当用含AD-exo的培养液和含UD-exo的培养液处理人皮肤成纤维细胞时,与阴性对照组相比,胶原的mRNA表达量增加,且显示与含AD-exo的培养液相比,在含UD-exo的培养液中胶原的mRNA表达量的增加更为显著(图7a)。
另外,为了从各经外泌体处理的人皮肤成纤维细胞获得的培养液内的胶原的定量,使用天狼星红总胶原检测试剂盒(Sirius Red Total Collagen Detection AssayKit,Cat#.9062P,Woodinville,USA)。将所述获得的上清液用0.05M乙酸缓冲液(aceticacid buffer)进行处理并在4℃保持12小时以上。之后,将所提供的胶原吸附染料(天狼星红染色液,sirius red solution)添加到添加有所述0.05M乙酸缓冲液的上清液中,以12,000rpm离心分离10分钟以浓缩胶原。之后,去除上清液以去除未吸附的染料,沉淀(pellet)用洗涤缓冲液清洗之后,离心分离10分钟以再一次浓缩胶原。之后,用碱性试剂(alkalireagent)处理,将吸附在胶原上的染料溶解,在530nm波长下测定吸光度。将吸光度代入标准曲线公式,计算添加UD-exo、AD-exo和阴性对照物质的孔中水溶性胶原的量。
其结果显示,UD-exo剂量组的水溶性胶原合成率比阴性对照组(190μg)有所提高,尤其是250μg/mL的UD-exo剂量组的胶原合成量为457μg,与同等量的AD-exo(211μg)相比其胶原合成量显著增加(图8b)。
由此证明从人体脂肪源干细胞中提取的外泌体具有促进皮肤成纤维细胞的胶原合成的效果。
实施例7.利用黑素细胞(melanocyte)的从人体尿源干细胞中提取的外泌体的酪
氨酸酶活性抑制效果
为了了解从人体尿源干细胞中提取的外泌体对酪氨酸酶活性抑制的影响,利用从人体尿源干细胞培养基中提取的外泌体(UD-exo)、从人体脂肪源干细胞培养基中提取的外泌体(AD-exo)进行酪氨酸酶活性抑制确认试验(Tyrosi nase inhibition assay、abcam、cat#2015)。使用250μg/mL的从人体尿源干细胞提取的外泌体和250μg/mL的从人体脂肪源干细胞提取的外泌体作为酪氨酸酶抑制样品。之后,在酪氨酸酶和酪氨酸酶底物反应后,添加每个外泌体样品,利用酶标仪,以未添加任何物质反应的阴性对照组为基准,每隔3分钟比较酪氨酸酶的活性,时间为30至60分钟。
其结果显示,用从人体尿源干细胞中提取的外泌体处理的组抑制34%的酪氨酸酶,用从人体脂肪源干细胞中提取的外泌体的组抑制16%的酪氨酸酶。由此证明从人体尿源干细胞中提取的外泌体的抑制酪氨酸酶活性的功效比从人体脂肪源干细胞中提取的外泌体更优异。
Claims (15)
1.一种皮肤再生、美白、抗氧化或治疗伤口用化妆品组合物,其包含尿源干细胞来源的外泌体作为有效成分。
2.根据权利要求1所述的化妆品组合物,其特征在于,
用于培养所述尿源干细胞的培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基即DMEM和哈姆F-12的基础培养基、2.5%以下的牛胎血清以及添加剂,
所述添加剂为选自由牛血清白蛋白、脂质混合物、成纤维细胞成长因子23即FGF23、三碘甲状腺原氨酸即T3以及骨化二醇组成的组中的一种以上。
3.根据权利要求2所述的化妆品组合物,其特征在于,
用于从所培养的所述尿源干细胞中提取外泌体的培养基组合物是无血清、无抗生素培养基组合物。
4.根据权利要求1所述的化妆品组合物,其特征在于,
所述尿源干细胞来源于自体、异体或者异种。
5.根据权利要求1所述的化妆品组合物,其特征在于,
所述伤口包括割伤、例如手术切口的切口、擦伤、撕裂伤或者撕裂、骨折、挫伤、烧伤或者截肢。
6.根据权利要求1所述的化妆品组合物,其特征在于,
所述化妆品组合物的剂型为爽肤水、柔肤水、护肤水、收敛剂、乳液、润肤乳、保湿乳、营养乳、按摩霜、营养霜、眼霜、保湿霜、护手霜、精华液、营养精华液、面膜、洗面奶、卸妆水、卸妆乳、洁面霜、身体乳、沐浴露、皂或者粉末。
7.一种皮肤再生、美白、抗氧化或治疗伤口用药物组合物,其包含尿源干细胞来源的外泌体作为有效成分。
8.根据权利要求7所述的药物组合物,其特征在于,
用于培养所述尿源干细胞的培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基即DMEM和哈姆F-12的基础培养基、2.5%以下的牛胎血清以及添加剂,
所述添加剂为选自由牛血清白蛋白、脂质混合物、成纤维细胞成长因子23即FGF23、三碘甲状腺原氨酸即T3以及骨化二醇组成的组中的一种以上。
9.根据权利要求8所述的药物组合物,其特征在于,
用于从所培养的所述尿源干细胞中提取外泌体的培养基组合物是无血清、无抗生素培养基组合物。
10.根据权利要求7所述的药物组合物,其特征在于,
所述尿源干细胞来源于自体、异体或者异种。
11.根据权利要求7所述的药物组合物,其特征在于,
所述伤口包括割伤、例如手术切口的切口、擦伤、撕裂伤或者撕裂、骨折、挫伤、烧伤或者截肢。
12.根据权利要求7所述的药物组合物,其特征在于,
所述药物组合物是选自霜、凝胶、软膏、皮肤乳化剂、皮肤悬浮液、透皮贴剂、面膜、含药物绷带或者乳液的皮肤外用剂。
13.一种用于皮肤再生、美白、抗氧化或治疗伤口的尿源干细胞来源的外泌体的制备方法,其中,所述方法包括:
在包括以3:1的比例包含杜尔贝科改良伊格尔培养基即DMEM和哈姆F-12的基础培养基、2.5%以下的牛胎血清以及添加剂的培养基组合物中培养尿源干细胞的步骤;以及
在无血清、无抗生素培养基组合物中培养所培养的所述尿源干细胞并提取外泌体的步骤。
14.根据权利要求13所述的方法,其特征在于,
所述添加剂包括牛血清白蛋白、脂质混合物、成纤维细胞成长因子23即FGF23、三碘甲状腺原氨酸即T3以及骨化二醇。
15.根据权利要求13所述的方法,其特征在于,
所述无血清、无抗生素培养基组合物包括以3:1的比例包含杜尔贝科改良伊格尔培养基即DMEM和哈姆F-12的基础培养基、成纤维细胞生长因子2即FGF2、皮质醇、三碘甲状腺原氨酸即T3、骨化三醇、胰岛素-转铁蛋白-硒-乙醇胺、L-抗坏血酸-2-磷酸酯以及视黄酸。
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