# Bone Marrow Mesenchymal Stem Cell‐Derived Exosomal Let‐7b‐5p Reduces High Glucose‐Induced Microglial Activation and Inflammation Through TLR4/ATF4

## TL;DR

This study shows that bone marrow stem cell-derived exosomes containing let-7b-5p can reduce inflammation in diabetic retinopathy by targeting a specific signaling pathway.

## Contribution

The study identifies let-7b-5p as a key miRNA in BMSC-derived exosomes that inhibits microglial activation via the TLR4/ATF4 pathway in diabetic retinopathy.

## Key findings

- BMSC-derived exosomes reduce microglial activation and inflammation in high glucose conditions.
- Let-7b-5p overexpression enhances the anti-inflammatory effects of BMSC exosomes in diabetic retinopathy.
- Let-7b-5p suppresses retinal damage by targeting the TLR4/ATF4 signaling pathway.

## Abstract

Diabetic retinopathy (DR) is a leading cause of vision loss in patients with diabetes mellitus (DM), and its pathogenesis is closely associated with aberrant microglial activation. Although bone marrow mesenchymal stem cell–derived exosomes (BMSC‐Exo) and the miRNAs that they carry show therapeutic potential for DR, the specific roles and molecular mechanisms through which let‐7b‐5p regulates microglial activation after it is delivered by BMSC‐Exo remain unclear. This study aimed to elucidate the function and underlying mechanism of BMSC‐Exo let‐7b‐5p in DR.

A DR mouse model was established by intraperitoneal injection of streptozotocin (STZ), and BV‐2 microglia were stimulated with high glucose (HG) to induce activation in vitro. The morphological characteristics of the BMSC‐Exo were identified using transmission electron microscopy (TEM). Protein and gene expression levels, as well as microglial activation, were assessed by Western blot, RT‐qPCR, and immunofluorescence, respectively. Retinal tissue damage and apoptosis were evaluated using HE staining and TUNEL assays.

BMSC‐Exo treatment significantly suppressed the expression of activation markers (Iba1 and TSPO) and inflammatory cytokines (TNF‐α, IL‐1β, and IL‐6) in HG‐induced BV‐2 cells and DR mouse retinas while alleviating retinal tissue damage and apoptosis. Bioinformatics analysis revealed the downregulation of let‐7b‐5p in DR. Functional experiments demonstrated that let‐7b‐5p overexpression enhanced the inhibitory effects of BMSC‐Exo on microglial activation, inflammation, and retinal damage, whereas let‐7b‐5p knockdown attenuated these therapeutic benefits. Mechanistically, BMSC‐Exo let‐7b‐5p inhibited excessive microglial activation and inflammatory responses by targeting the TLR4/ATF4 signaling pathway.

BMSC‐Exo deliver let‐7b‐5p to suppress the TLR4/ATF4 pathway, thereby mitigating microglial activation and inflammation and ultimately delaying DR progression. These findings support the potential of this novel therapeutic strategy for targeted DR treatment.