Extracellular vesicles derived from TNF-α-preconditioned mesenchymal stem cells mitigate inflammatory retinal injury

Area of Science:

• Regenerative Medicine
• Ophthalmology
• Immunology

Background:

• Inflammatory retinal injuries pose significant challenges to vision preservation.
• Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (sEVs) are explored for therapeutic potential.
• Understanding the mechanisms of sEVs in mitigating retinal inflammation is crucial.

Purpose of the Study:

• To evaluate the therapeutic efficacy of TNF-α preconditioned MSCs-derived small extracellular vesicles (T-sEV) in inflammatory retinal injury.
• To elucidate the mechanisms by which T-sEV mitigate M1 macrophage polarization and protect the retina.
• To compare the efficacy of T-sEV with control sEVs from naive MSCs.

Main Methods:

• Isolation and characterization of T-sEV and sEV.
• Small RNA sequencing to identify miRNA cargo of T-sEV.
• Assessment of T-sEV's effect on M1 macrophage polarization in vitro.
• Intravitreal administration of T-sEV in a murine sodium iodate-induced retinal degeneration model.
• Evaluation of retinal function (ERG), structure (OCT), macrophage infiltration, and intraocular pressure.

Main Results:

• T-sEVs are enriched with anti-inflammatory miRNAs, notably miR-146a-5p.
• T-sEVs significantly suppressed M1 macrophage polarization in vitro and reduced retinal macrophage infiltration in vivo.
• T-sEV treatment preserved retinal function (a- and b-wave amplitudes) and structural integrity.
• No adverse effects on intraocular pressure or systemic markers were observed.

Conclusions:

• TNF-α preconditioning enhances the therapeutic capacity of MSC-derived sEVs by enriching anti-inflammatory miRNAs.
• T-sEVs offer a promising cell-free therapeutic strategy for inflammatory retinal degeneration by modulating macrophage activation.
• T-sEVs demonstrate superior neuroprotection and safety in a preclinical model of retinal injury.