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Abstract
Mesenchymal stem cells (MSCs) transfer healthy mitochondria to damaged acceptor cells via actin-based intercellular structures. In this study, we tested the hypothesis that MSCs transfer mitochondria to neural stem cells (NSCs) to protect NSCs against the neurotoxic effects of cisplatin treatment. Our results show that MSCs donate mitochondria to NSCs damaged in vitro by cisplatin. Transfer of healthy MSC-derived mitochondria decreases cisplatin-induced NSC death. Moreover, mitochondrial transfer from MSCs to NSCs reverses the cisplatin-induced decrease in mitochondrial membrane potential. Blocking the formation of actin-based intercellular structures inhibited the transfer of mitochondria to NSCs and abrogated the positive effects of MSCs on NSC survival. Conversely, overexpression of the mitochondrial motor protein Rho-GTPase 1 (Miro1) in MSCs increased mitochondrial transfer and further improved survival of cisplatin-treated NSCs.In vivo, MSC administration prevented the loss of DCX+ neural progenitor cells in the subventricular zone and hippocampal dentate gyrus which occurs as a result of cisplatin treatment. We propose mitochondrial transfer as one of the mechanisms via which MSCs exert their therapeutic regenerative effects after cisplatin treatment.
Highlights
Mesenchymal stem cells (MSCs) have been shown to stimulate tissue repair in various disease models, including cardiomyopathy, pulmonary damage, cerebral ischemic insults, and neurodegenerative disorders like Alzheimer and Parkinson disease [8]
Here we show for the first time that MSCs donate mitochondria to Neuronal stem cell (NSC) when damaged by cisplatin in vitro
We show for the first time that the loss of DCX+ neuronal precursors caused by administration of 2 cycles of cisplatin can be rescued by intranasal administration of MSCs
Summary
Mesenchymal stem cells (MSCs) have been shown to stimulate tissue repair in various disease models, including cardiomyopathy, pulmonary damage, cerebral ischemic insults, and neurodegenerative disorders like Alzheimer and Parkinson disease [8]. MSCs transfer mitochondria to cardiomyocytes in a model of anthracycline-induced cardiomyopathy [46], to murine alveoli in acute lung injury [17], to murine lung epithelial cells in rotenone-induced airway injury [2], to cortical neurons in a model of cerebral stroke [5]. Increasing evidence indicates that cognitive deficits develop in cancer patients treated with chemotherapy. Cognitive deficits induced by cancer treatment are characterized by confusion, memory loss, reduced attention and processing speed, and decreased executive functioning [20,21,22, 39, 43]. Longitudinal neuropsychological studies report that up to 75% of cancer patients experience cognitive problems during treatment and likely 35% of affected cancer patients have long-term cognitive effects that seriously impair their quality of life [1]
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