Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization

Journal of Nanobiotechnology

Research

Pan Liu¹  Hui-ping Yuan¹  Yan Zhang²  Wan-yun Qin²  Zheng-bo Shao²  Xiang-hui Li²  Yu-hang Zhou²  Yuan Wang²  Xin-qi Ye²  Ying Bai²  Xin-lin Wang²  Qi Wang³  Xin-na Liu³ 

[1] Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China;The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry Education, Harbin, China;

关键词: Exosomes;    Bone marrow Sca-1 cell;    Ischemia/reperfusion injury;    miR-150-5p;    MEKK3;   

DOI  :  10.1186/s12951-023-01944-w

 received in 2023-03-24, accepted in 2023-05-29,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPolarization of microglia, the resident retinal immune cells, plays important roles in mediating both injury and repair responses post-retinal ischemia–reperfusion (I/R) injury, which is one of the main pathological mechanisms behind ganglion cell apoptosis. Aging could perturb microglial balances, resulting in lowered post-I/R retinal repair. Young bone marrow (BM) stem cell antigen 1-positive (Sca-1+) cells have been demonstrated to have higher reparative capabilities post-I/R retinal injury when transplanted into old mice, where they were able to home and differentiate into retinal microglia.MethodsExosomes were enriched from young Sca-1+ or Sca-1− cells, and injected into the vitreous humor of old mice post-retinal I/R. Bioinformatics analyses, including miRNA sequencing, was used to analyze exosome contents, which was confirmed by RT-qPCR. Western blot was then performed to examine expression levels of inflammatory factors and underlying signaling pathway proteins, while immunofluorescence staining was used to examine the extent of pro-inflammatory M1 microglial polarization. Fluoro-Gold labelling was then utilized to identify viable ganglion cells, while H&E staining was used to examine retinal morphology post-I/R and exosome treatment.ResultsSca-1+ exosome-injected mice yielded better visual functional preservation and lowered inflammatory factors, compared to Sca-1−, at days 1, 3, and 7 days post-I/R. miRNA sequencing found that Sca-1+ exosomes had higher miR-150-5p levels, compared to Sca-1− exosomes, which was confirmed by RT-qPCR. Mechanistic analysis found that miR-150-5p from Sca-1+ exosomes repressed the mitogen-activated protein kinase kinase kinase 3 (MEKK3)/JNK/c-Jun axis, leading to IL-6 and TNF-α downregulation, and subsequently reduced microglial polarization, all of which contributes to reduced ganglion cell apoptosis and preservation of proper retinal morphology.ConclusionThis study elucidates a potential new therapeutic approach for neuroprotection against I/R injury, via delivering miR-150-5p-enriched Sca-1+ exosomes, which targets the miR-150-5p/MEKK3/JNK/c-Jun axis, thereby serving as a cell-free remedy for treating retinal I/R injury and preserving visual functioning.

【 授权许可】

CC BY   
© The Author(s) 2023. corrected publication 2023

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