Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L-mitophagy pathway.
Jun Hee LeeYeo Min YoonKeon-Hyoung SongHyunjin NohSang-Hun LeePublished in: Aging cell (2020)
Mesenchymal stem cells (MSCs) are a popular cell source for stem cell-based therapy. However, continuous ex vivo expansion to acquire large amounts of MSCs for clinical study induces replicative senescence, causing decreased therapeutic efficacy in MSCs. To address this issue, we investigated the effect of melatonin on replicative senescence in MSCs. In senescent MSCs (late passage), replicative senescence decreased mitophagy by inhibiting mitofission, resulting in the augmentation of mitochondrial dysfunction. Treatment with melatonin rescued replicative senescence by enhancing mitophagy and mitochondrial function through upregulation of heat shock 70 kDa protein 1L (HSPA1L). More specifically, we found that melatonin-induced HSPA1L binds to cellular prion protein (PrPC ), resulting in the recruitment of PrPC into the mitochondria. The HSPA1L-PrPC complex then binds to COX4IA, which is a mitochondrial complex IV protein, leading to an increase in mitochondrial membrane potential and anti-oxidant enzyme activity. These protective effects were blocked by knockdown of HSPA1L. In a murine hindlimb ischemia model, melatonin-treated senescent MSCs enhanced functional recovery by increasing blood flow perfusion, limb salvage, and neovascularization. This study, for the first time, suggests that melatonin protects MSCs against replicative senescence during ex vivo expansion for clinical application via mitochondrial quality control.
Keyphrases
- mesenchymal stem cells
- umbilical cord
- heat shock protein
- dna damage
- endothelial cells
- heat shock
- cell therapy
- bone marrow
- blood flow
- stress induced
- oxidative stress
- stem cells
- quality control
- high glucose
- signaling pathway
- protein protein
- poor prognosis
- cell proliferation
- cell death
- clinical trial
- magnetic resonance imaging
- amino acid
- diabetic rats
- high resolution
- heat stress
- magnetic resonance
- newly diagnosed
- smoking cessation
- combination therapy
- atomic force microscopy
- diabetic retinopathy