MicroRNAs of extracellular vesicles derived from mesenchymal stromal cells alleviate inflammation in dry eye disease by targeting the IRAK1/TAB2/NF-κB pathway

Leying Wang; Xueyao Wang; Qiankun Chen; Zhenyu Wei; Xizhan Xu; Deqiang Han; Yuheng Zhang; Zhiguo Chen; Qingfeng Liang

doi:10.1016/j.jtos.2023.03.002

MicroRNAs of extracellular vesicles derived from mesenchymal stromal cells alleviate inflammation in dry eye disease by targeting the IRAK1/TAB2/NF-κB pathway

Ocul Surf. 2023 Apr:28:131-140. doi: 10.1016/j.jtos.2023.03.002. Epub 2023 Mar 27.

Authors

Leying Wang¹, Xueyao Wang², Qiankun Chen¹, Zhenyu Wei¹, Xizhan Xu¹, Deqiang Han², Yuheng Zhang¹, Zhiguo Chen³, Qingfeng Liang⁴

Affiliations

¹ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, 100005, China.
² Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, And Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China.
³ Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases, And Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China. Electronic address: chenzhiguo@gmail.com.
⁴ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, 100005, China. Electronic address: liangqingfeng@ccmu.edu.cn.

PMID: 36990276
DOI: 10.1016/j.jtos.2023.03.002

Abstract

Purpose: To investigate the efficacy and mechanisms of human umbilical cord-derived MSC-derived extracellular vesicles (hucMSC-EVs) in a mouse model of desiccation-induced dry eye disease (DED).

Methods: hucMSC-EVs were enriched by ultracentrifugation. The DED model was induced by desiccating environment combined with scopolamine administration. The DED mice were divided into the hucMSC-EVs group, fluorometholone (FML) group, PBS group, and blank control group. Tear secretion, corneal fluorescein staining, the cytokine profiles in tears and goblet cells, TUNEL-positive cell, and CD4⁺ cells were examined to assess therapeutic efficiency. The miRNAs in the hucMSC-EVs were sequenced, and the top 10 were used for miRNA enrichment analysis and annotation. The targeted DED-related signaling pathway was further verified by using RT‒qPCR and western blotting.

Results: Treatment with hucMSC-EVs increased the tear volume and maintained corneal integrity in DED mice. The cytokine profile in the tears of the hucMSC-EVs group presented with a lower level of proinflammatory cytokines than PBS group. Moreover, hucMSC-EVs treatment increased goblet cell density and inhibited cell apoptosis and CD4⁺ cell infiltration. Functional analysis of the top 10 miRNAs in hucMSC-EVs showed a high correlation with immunity. Among them, miR-125 b, let-7b, and miR-6873 were conserved between humans and mice and were associated with the IRAK1/TAB2/NF-κB pathway that was activated in DED. Furthermore, IRAK1/TAB2/NF-κB pathway activation and the abnormal expression of IL-4, IL-8, IL-10, IL-13, IL-17, and TNF-α were reversed by hucMSC-EVs.

Conclusions: hucMSCs-EVs alleviate DED signs, suppress inflammation and restore homeostasis of the corneal surface by multitargeting the IRAK1/TAB2/NF-κB pathway via certain miRNAs.

Keywords: Dry eye; Extracellular vesicles; Immunomodulatory; Mesenchymal stromal cells; Treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / metabolism
Adaptor Proteins, Signal Transducing / therapeutic use
Animals
Cytokines / metabolism
Dry Eye Syndromes* / metabolism
Extracellular Vesicles* / metabolism
Humans
Inflammation / metabolism
Interleukin-1 Receptor-Associated Kinases / genetics
Interleukin-1 Receptor-Associated Kinases / metabolism
Interleukin-1 Receptor-Associated Kinases / therapeutic use
Mesenchymal Stem Cells*
Mice
MicroRNAs* / genetics
NF-kappa B / metabolism
NF-kappa B / therapeutic use

Substances

MicroRNAs
NF-kappa B
Cytokines
IRAK1 protein, human
Interleukin-1 Receptor-Associated Kinases
TAB2 protein, human
Adaptor Proteins, Signal Transducing