Adipose-derived stem cell exosomes promote neurological recovery after subarachnoid hemorrhage via AMPK/mTOR-mediated TFEB activation

BACKGROUND: Subarachnoid hemorrhage (SAH) is a common neurologically devastating disorder, and existing treatment options remain very limited. Increasing evidence has confirmed the neuroprotective effects of exosomes derived from mesenchymal stem cells (MSC). Our work investigates that adipose-derived stem cell exosomes (ADSC-Exos) exert therapeutic effects against SAH through autophagy-related pathways. METHODS: An intracerebral perforation method was used to establish a rat SAH model. Then we injected PBS containing 50 µg, 100 µg, or 200 µg of exosomes. Rat neurological deficits and brain water content were assessed. Additionally, brain tissues were collected for Nissl staining, immunofluorescence and Western blot analysis. Furthermore, we utilized oxyhemoglobin (OxyHb) to induce an in vitro SAH model in primary neurons. BML-275 (an AMPK inhibitor) was administered to explore the mechanism of ADSC-Exos-induced autophagy. RESULTS: ADSC-Exos reduced neurological deficits and brain water content in rats with SAH, while also inhibiting neuronal apoptosis. Treatment with ADSC-Exos led to an increase in Beclin1 and LC3 levels. Both Western blot and immunofluorescence analyses revealed that the TFEB nuclear translocation activated after ADSC-Exos treatment. What's more, the level of P-AMPKα/AMPK was increased and P-MTOR/mTOR was decreased. On the other hand, the administration of BML-275 was able to reverse these effects of ADSC-Exos. CONCLUSION: In summary, these results suggest that ADSC-Exos may exert neuroprotective effects in the SAH rat model through autophagy pathways, involving AMPK/mTOR-dependent TFEB nuclear translocation that induces autophagy. These findings may provide a potential therapeutic strategy for SAH.