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负载外泌体的温敏水凝胶用于角膜上皮和基质再生。

Exosomes-loaded thermosensitive hydrogels for corneal epithelium and stroma regeneration.

机构信息

Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou, 310009, China.

Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310009, China.

出版信息

Biomaterials. 2022 Jan;280:121320. doi: 10.1016/j.biomaterials.2021.121320. Epub 2021 Dec 11.

Abstract

Corneal damage forms scar tissue and manifests as permanent corneal opacity, which is the main cause of visual impairment caused by corneal diseases. To treat these diseases, herein, we developed a novel approach based on the exosome derived from induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) combined with a thermosensitive hydrogel, which reduces scar formation and accelerates the healing process. We found that a thermosensitive chitosan-based hydrogels (CHI hydrogel) sustained-release iPSC-MSC exosomes can effectively promote the repair of damaged corneal epithelium and stromal layer, downregulating mRNA expression coding for the three most enriched collagens (collagen type I alpha 1, collagen type V alpha 1 and collagen type V alpha 2) in corneal stroma and reducing scar formation in vivo. Furthermore, iPSC-MSCs secrete exosomes that contain miR-432-5p, which suppresses translocation-associated membrane protein 2 (TRAM2), a vital modulator of the collagen biosynthesis in the corneal stromal stem cells to avert the deposition of extracellular matrix (ECM). Our findings indicate that iPSC-MSCs secrete miRNA-containing exosomes to promote corneal epithelium and stroma regeneration, and that miR-432-5p can prevent ECM deposition via a mechanism most probably linked to direct repression of its target gene TRAM2. Overall, our exosomes-based thermosensitive CHI hydrogel, is a promising technology for clinical therapy of various corneal diseases.

摘要

角膜损伤形成瘢痕组织,并表现为永久性角膜混浊,这是由角膜疾病引起视力损害的主要原因。为了治疗这些疾病,我们在此开发了一种基于诱导多能干细胞衍生的间充质干细胞(iPSC-MSCs)衍生的外体与温敏水凝胶相结合的新方法,该方法可减少瘢痕形成并加速愈合过程。我们发现,一种温敏壳聚糖基水凝胶(CHI 水凝胶)持续释放 iPSC-MSC 外体可有效促进受损角膜上皮和基质层的修复,下调编码角膜基质中最丰富的三种胶原蛋白(I 型胶原α 1、V 型胶原α 1 和 V 型胶原α 2)的 mRNA 表达,并减少体内瘢痕形成。此外,iPSC-MSCs 分泌含有 miR-432-5p 的外体,miR-432-5p 抑制易位相关膜蛋白 2(TRAM2),TRAM2 是角膜基质干细胞中胶原蛋白生物合成的重要调节剂,可防止细胞外基质(ECM)的沉积。我们的研究结果表明,iPSC-MSCs 通过分泌含有 miRNA 的外体来促进角膜上皮和基质再生,而 miR-432-5p 通过一种可能与直接抑制其靶基因 TRAM2 相关的机制来防止 ECM 沉积。总的来说,我们基于外体的温敏 CHI 水凝胶是治疗各种角膜疾病的有前途的临床治疗技术。

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