人脂肪和脐带间充质干细胞衍生的细胞外囊泡通过TIMP1/Notch1减轻光老化-动脉网

Human adipose and umbilical cord mesenchymal stem cell-derived extracellular vesicles mitigate photoaging via TIMP1/Notch1

Nature 等信源发布 2024-10-30 07:44

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AbstractUVB radiation induces oxidative stress, DNA damage, and inflammation, leading to skin wrinkling, compromised barrier function, and an increased risk of carcinogenesis. Addressing or preventing photoaging may offer a promising therapeutic avenue for these conditions. Recent research indicated that mesenchymal stem cells (MSCs) exhibit significant therapeutic potential for various skin diseases.

摘要UVB辐射诱导氧化应激，DNA损伤和炎症，导致皮肤起皱，屏障功能受损，致癌风险增加。解决或预防光老化可能为这些疾病提供有希望的治疗途径。最近的研究表明，间充质干细胞（MSCs）对各种皮肤疾病具有显着的治疗潜力。

Given that extracellular vesicles (EV) can deliver diverse cargo to recipient cells and elicit similar therapeutic effects, we investigated the roles and underlying mechanisms of both adipose-derived MSC-derived EV (AMSC-EV) and umbilical cord-derived MSC-derived EV (HUMSC-EV) in photoaging. Our findings indicated that in vivo, treatment with AMSC-EV and HUMSC-EV resulted in improvements in wrinkles and skin hydration while also mitigating skin inflammation and thickness alterations in both the epidermis and dermis.

鉴于细胞外囊泡（EV）可以向受体细胞递送多种货物并引发相似的治疗效果，我们研究了脂肪来源的MSC衍生的EV（AMSC-EV）和脐带来源的MSC衍生的EV（HUMSC-EV）在光老化中的作用和潜在机制。我们的研究结果表明，在体内，用AMSC-EV和HUMSC-EV治疗可改善皱纹和皮肤水合作用，同时减轻皮肤炎症和表皮和真皮厚度的改变。

Additionally, in vitro studies using human keratinocytes (HaCaTs), human dermal fibroblast cells (HDFs), and T-Skin models revealed that AMSC-EV and HUMSC-EV attenuated senescence, reduced levels of reactive oxygen species (ROS) and DNA damage, and alleviated inflammation induced by UVB. Furthermore, EV treatment enhanced cell viability and migration capacity in the epidermis and promoted extracellular matrix (ECM) remodeling in the dermis in photoaged cell models.

此外，使用人角质形成细胞（HaCaTs），人皮肤成纤维细胞（HDF）和T皮肤模型的体外研究表明，AMSC-EV和HUMSC-EV可减轻衰老，降低活性氧（ROS）水平和DNA损伤，并减轻UVB诱导的炎症。此外，EV处理增强了表皮中的细胞活力和迁移能力，并促进了光老化细胞模型中真皮中的细胞外基质（ECM）重塑。

Mechanistically, proteomics results showed that TIMP1 was highly expressed in both AMSC-EV and HUMSC-EV and could exert similar effects as MSC-EV. In addition, we found that EV and TIMP1 could inhibit Notch1 and downstream targets Hes1, P16, P21, and P53. Collectively, our data suggests that both AMSC-EV and HUMSC-EV attenuate skin photoaging through TIMP1/Notch1..

从机制上讲，蛋白质组学结果显示TIMP1在AMSC-EV和HUMSC-EV中均高表达，并且可以发挥与MSC-EV相似的作用。此外，我们发现EV和TIMP1可以抑制Notch1和下游靶标Hes1，P16，P21和P53。总的来说，我们的数据表明AMSC-EV和HUMSC-EV都通过TIMP1/Notch1减弱皮肤光老化。。

IntroductionHuman skin, the body’s largest organ, serves as the primary barrier against environmental factors, especially solar ultraviolet (UV) radiation.1 UV is divided into UVA (320–400 nm), UVB (280–20 nm), and UVC (280–100 nm) based on wavelength. UVC is absorbed by the stratospheric ozone layer and does not reach the earth.

简介人体最大的器官皮肤是抵抗环境因素的主要屏障，特别是太阳紫外线（UV）辐射。紫外线根据波长分为UVA（320-400nm），UVB（280-20nm）和UVC（280-100nm）。UVC被平流层臭氧层吸收，不会到达地球。

Relative to UVA, UVB has less penetrating ability into the skin but a greater damaging effect.2 UVB exposure increases the risk of various skin disorders leading to tanning, and inflammatory reactions including redness and blistering in the short term.3 In the long term, it can lead to photoaging including wrinkles, decreased barrier capacity and resilience, and an increased risk of carcinogenesis such as keratinocyte carcinoma, basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma.4 It is reported that nearly 80% of adults aged 70 and above suffer from one or more skin diseases that require further treatment or follow-up, including UV-induced skin diseases such as Lentigo senilis (69.5%), actinic keratosis (22.3%), Basal cell carcinoma (5.07%), Melanoma (0.54%) and Squamous cell carcinoma (0.36%).5 Therefore, an in-depth understanding of UVB-induced skin damage, molecular mechanisms, and therapeutic options is of great scientific importance and clinical value.

。

Currently, there are several traditional treatments for photoaging, including the use of retinoids, antioxidant products, or optical therapies; however, some strategies are not always effective or can cause side effects, such as allergy or irritation.6,7 An effective treatment program with few side effects is therefore needed.Extracellular vesicles (EV) are lipid bilayer membrane-delimited particles with functional components such as proteins and microRNAs (miRNAs).8 They.

目前，有几种传统的光老化治疗方法，包括使用类维生素A，抗氧化产品或光学疗法；然而，一些策略并不总是有效的，或者可能会引起副作用，如过敏或刺激。因此，需要一种副作用少的有效治疗方案。细胞外囊泡（EV）是脂质双层膜界定的颗粒，具有蛋白质和microRNA（miRNA）等功能成分。

Data availability

数据可用性

All data supporting this paper are present within the paper and/or the Supplementary Materials. The original datasets are also available from the corresponding author upon request. The raw data of RNA-seq presented in this study have been deposited in the NCBI Web site (https://www.ncbi.nlm.nih.gov), under the project number PRJNA1164396.

支持本文的所有数据都包含在论文和/或补充材料中。原始数据集也可根据要求从通讯作者处获得。本研究中提供的RNA-seq的原始数据已保存在NCBI网站上(https://www.ncbi.nlm.nih.gov)，项目编号为PRJNA1164396。

The proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD056371..

蛋白质组学数据已通过PRIDE合作伙伴存储库保存到ProteomeXchange Consortium，数据集标识符为PXD056371。。

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Xiao, W. et al. TIMP-1 dependent modulation of metabolic profiles impacts chemoresistance in NSCLC. Cells 11, 3036 (2022).Download referencesAcknowledgementsThis study was supported by the CAMS Initiative for Innovative Medicine (2022-I2M-1-012), the 111 Project (B18007), National Key R&D Program of China (2020YFA0113000), Key-Area Research and Development Program of Guangdong Province (2021B0909060001), 2021 General Research Institute for Nonferrous Metals ‘Unveiling and Commanding’ Project (2021JC0103).Author informationAuthor notesThese authors contributed equally: Huan Zhang, Xian XiaoAuthors and AffiliationsInstitute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, ChinaHuan Zhang, Xian Xiao, Liping Wang, Xianhao Shi, Nan Fu, Shihua Wang & Robert Chunhua ZhaoDepartment of Cell Biology, School of Life Sciences, Shanghai University, Shanghai, ChinaRobert Chunhua ZhaoAuthorsHuan ZhangView author publicationsYou can also search for this author in.

Xiao，W。等人。TIMP-1依赖性代谢谱调节影响NSCLC的化学耐药性。细胞113036（2022）。下载参考文献致谢本研究得到了CAMS创新医学倡议（2022-I2M-1-012），111项目（B18007），国家重点研发计划（2020YFA0113000），广东省重点领域研究与发展计划（2021B090906001），2021有色金属总研究所“揭幕与指挥”项目（2021JC0103）的支持。作者信息作者注意到这些作者做出了同样的贡献：张欢，冼晓作者和附属机构中国医学科学院基础医学研究所，北京协和医科大学基础医学院，北京，中国张欢，冼晓，王丽萍，史先浩，傅楠，王世华和赵春华上海大学生命科学学院细胞生物学系赵春华作者张欢观点作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarXian XiaoView作者出版物您也可以在

PubMed Google ScholarLiping WangView author publicationsYou can also search for this author in

PubMed Google ScholarLiping WangView作者出版物您也可以在

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PubMed Google ScholarNan FuView作者出版物您也可以在

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PubMed Google ScholarContributionsH.Z. and X.X. performed and analyzed experiments, prepared the figures, and wrote the manuscript. S.W. designed and analyzed experiments and wrote the manuscript. L.W., X.S., and N.F. performed the experiments. R.C.Z. designed the experiment.

PubMed谷歌学术贡献。Z、和X.X.进行并分析了实验，准备了数字并撰写了手稿。S、 W.设计并分析了实验并撰写了手稿。五十、 W.，X.S。和N.F.进行了实验。R、 C.Z.设计了这个实验。

All authors have read and approved the final manuscript.Corresponding authorsCorrespondence to.

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Reprints and permissionsAbout this articleCite this articleZhang, H., Xiao, X., Wang, L. et al. Human adipose and umbilical cord mesenchymal stem cell-derived extracellular vesicles mitigate photoaging via TIMP1/Notch1.

转载和许可本文引用本文Zhang，H.，Xiao，X.，Wang，L。等人。人脂肪和脐带间充质干细胞衍生的细胞外囊泡通过TIMP1/Notch1减轻光老化。

Sig Transduct Target Ther 9, 294 (2024). https://doi.org/10.1038/s41392-024-01993-zDownload citationReceived: 23 April 2024Revised: 13 September 2024Accepted: 26 September 2024Published: 30 October 2024DOI: https://doi.org/10.1038/s41392-024-01993-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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