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光遗传学工程脐带间充质干细胞衍生的外泌体用于重塑糖尿病创面免疫微环境和促进组织修复。

Optogenetic engineered umbilical cord MSC-derived exosomes for remodeling of the immune microenvironment in diabetic wounds and the promotion of tissue repair.

机构信息

General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, 310014, China.

College of Pharmacy, Hangzhou Medical College, Hangzhou, 310059, China.

出版信息

J Nanobiotechnology. 2023 Jun 2;21(1):176. doi: 10.1186/s12951-023-01886-3.

DOI:10.1186/s12951-023-01886-3
PMID:37269014
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10236791/
Abstract

BACKGROUND

Angiogenesis and tissue repair in chronic non-healing diabetic wounds remain critical clinical problems. Engineered MSC-derived exosomes have significant potential for the promotion of wound healing. Here, we discuss the effects and mechanisms of eNOS-rich umbilical cord MSC exosomes (UCMSC-exo/eNOS) modified by genetic engineering and optogenetic techniques on diabetic chronic wound repair.

METHODS

Umbilical cord mesenchymal stem cells were engineered to express two recombinant proteins. Large amounts of eNOS were loaded into UCMSC-exo using the EXPLOR system under blue light irradiation. The effects of UCMSC-exo/eNOS on the biological functions of fibroblasts and vascular endothelial cells in vitro were evaluated. Full-thickness skin wounds were constructed on the backs of diabetic mice to assess the role of UCMSC-exo/eNOS in vascular neogenesis and the immune microenvironment, and to explore the related molecular mechanisms.

RESULTS

eNOS was substantially enriched in UCMSCs-exo by endogenous cellular activities under blue light irradiation. UCMSC-exo/eNOS significantly improved the biological functions of cells after high-glucose treatment and reduced the expression of inflammatory factors and apoptosis induced by oxidative stress. In vivo, UCMSC-exo/eNOS significantly improved the rate of wound closure and enhanced vascular neogenesis and matrix remodeling in diabetic mice. UCMSC-exo/eNOS also improved the inflammatory profile at the wound site and modulated the associated immune microenvironment, thus significantly promoting tissue repair.

CONCLUSION

This study provides a novel therapeutic strategy based on engineered stem cell-derived exosomes for the promotion of angiogenesis and tissue repair in chronic diabetic wounds.

摘要

背景

血管生成和慢性难愈性糖尿病创面组织修复仍然是临床亟待解决的关键问题。工程化 MSC 来源的外泌体在促进创面愈合方面具有显著的应用潜力。本文探讨了基因工程和光遗传学技术修饰的 eNOS 丰富的脐带 MSC 外泌体（UCMSC-exo/eNOS）对糖尿病慢性创面修复的作用及其机制。

方法

通过基因工程使脐带间充质干细胞表达两种重组蛋白。使用 EXPLOR 系统在蓝光照射下将大量 eNOS 载入 UCMSC-exo。评估 UCMSC-exo/eNOS 对体外成纤维细胞和血管内皮细胞生物学功能的影响。在糖尿病小鼠背部构建全层皮肤创面，评估 UCMSC-exo/eNOS 在血管新生和免疫微环境中的作用，并探讨相关分子机制。

结果

蓝光照射下，UCMSC-exo 中内源性细胞活动可显著富集 eNOS。UCMSC-exo/eNOS 可显著改善高糖处理后细胞的生物学功能，降低氧化应激诱导的炎症因子表达和细胞凋亡。在体内，UCMSC-exo/eNOS 可显著提高糖尿病小鼠创面的愈合率，促进血管新生和基质重塑。UCMSC-exo/eNOS 还可改善创面部位的炎症表型，调节相关免疫微环境，从而显著促进组织修复。

结论

本研究为基于工程化干细胞来源的外泌体促进慢性糖尿病创面血管生成和组织修复提供了一种新的治疗策略。

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