Dental pulp stem cell secretome inhibits mitophagy-induced hippocampal neural injury during hypoxia

Abstract

Hypoxic stress induces neuronal damage by increasing mitochondrial reactive oxygen species (mtROS), triggering mitophagy-associated cell death, and promoting neuroinflammation. However, the neuroprotective potential of human dental pulp stem cell (hDPSC) secretome in this process remains unclear. Here, we show that the hDPSC secretome mitigates hypoxic stress-induced neuronal injury by modulating mitophagy and inflammatory pathways. Proteomic analysis revealed key therapeutic proteins in the hDPSC secretome, which appear to reduce mtROS levels and suppress mitophagy markers, including PHB2, BCL2L13, BNIP3, and LC3-II. CoCl2-induced activation of the TLR4-NF-kappa B pathway increased pro-inflammatory cytokines, promoting cell death, but the hDPSC secretome inhibited this activation while enhancing anti-apoptotic proteins to support neuronal survival. Furthermore, the hDPSC secretome restored neuronal and synaptic markers, including neurofilament heavy chain, synaptophysin, and PSD95, contributing to neuronal recovery and synaptic integrity. This study provides evidence that the hDPSC secretome alleviates hypoxic stress-induced neuronal damage through a multifaceted neuroprotective mechanism. These findings indicate its potential as a therapeutic strategy for neurodegenerative conditions.