Overexpression of Heme Oxygenase 1 Enhances the Neuroprotective Effects of Exosomes in Subarachnoid Hemorrhage by Suppressing Oxidative Stress and Endoplasmic Reticulum Stress

This study aims to elucidate the therapeutic effects and underlying mechanisms of exosomes derived from Heme oxygenase 1 (HO-1)-overexpressing human umbilical cord mesenchymal stem cells (Exo^HO−1) in a subarachnoid hemorrhage (SAH) mouse model.

In this study, exosomes were identified using Western blotting, particle analysis, and transmission electron microscopy. The effect of Exo^HO−1 and Exo^Ctrl on the neurological function of SAH mice was assessed using the Garcia scoring system, Beam balance, Rotarod test, and Morris water maze test. Neuronal apoptosis and survival were evaluated through TUNEL and Nissl staining. Levels of oxidative and endoplasmic reticulum stress were measured via immunofluorescence, Western blotting, DHE staining, enzyme-linked immunosorbent assay, and commercial kits.

HO-1-overexpressing human umbilical cord mesenchymal stem cells encapsulated HO-1 into their exosomes. Exo^HO−1 significantly enhanced both short-term and long-term neurological function protection. By reducing the activation of the PERK/CHOP/Caspase12 pathway and decreasing oxidative stress levels, Exo^HO−1 effectively inhibited neuronal apoptosis in the ipsilateral temporal cortex.

Exo^HO−1 enhances the therapeutic efficacy of exosomes in SAH mice by countering neuronal apoptosis, primarily through the suppression of oxidative and endoplasmic reticulum stress.

Schematic drawing of neuroprotective effects of Exo^HO-1. After SAH, Exo^HO-1 exhibited enhanced inhibitory effects on neuroinflammation and neuronal apoptosis. Those effects partially through inhibiting endoplasmic reticulum stress and oxidative stress following SAH