Nasal Mesenchymal Stem Cell Treatment for the Repair of Chemotherapy-Induced Neurotoxicities: Let the Trojan Horse In!

Abstract

In this thesis, we show for the first time that nasal administration of mesenchymal stem cells (MSC) promotes recovery from chemotherapy-induced cognitive impairment and chemotherapy-induced peripheral neuropathy (CIPN), two major side effects of cancer treatment that frequently persist long into survivorship. We demonstrate that nasal administration of MSC reverses cognitive impairments induced by cisplatin treatment in mice. Resting state functional magnetic resonance imaging study of network connectivity in the brain shows that cisplatin treatment leads to a decrease in global neuronal connectivity. Connectome analysis reveals a decrease in path length in cisplatin-treated mice, which is reversed by MSC treatment. Functionally, nasally administered MSC reversed cisplatin-induced synaptosomal mitochondrial dysfunction and abnormal mitochondrial morphology. Moreover, MSC reversed cisplatin-induced morphological changes of cortical white matter structures. RNA sequencing analysis revealed mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice, supporting the concept that MSC may act by resolving neuronal mitochondrial dysfunction leading to restoration of the cognitive deficits and associated brain damage after chemotherapy. We show that cisplatin treatment leads to mitochondrial dysfunction and death of neural stem cells (NSC) in vitro as well as a decrease in the number of Doublecortin (DCX)+ neural progenitor cells in the brain neurogenic niches. Nasal MSC treatment rescues damaged NSC from cell death in vitro and reverses the loss of DCX+ cells in vivo. Furthermore, we show that MSC donate mitochondria to NSC damaged by cisplatin in vitro, contributing to the beneficial effects of MSC in rescuing damaged NSC. Mitochondrial transfer is potentiated by overexpression of the Rho-GTPase Miro1. Moreover, mitochondrial transfer from MSC to NSC is associated with restoration of mitochondrial membrane potential and protection against cisplatin-induced cell death. Interestingly, we also demonstrate that nasal MSC administration resolves symptoms of CIPN, including mechanical allodynia and spontaneous pain. Nasal MSC treatment normalizes cisplatin-induced mitochondrial dysfunction in DRG neurons as well as tibial nerves and reverses the retraction of peripheral nerves endings in the paw of cisplatin-treated mice. As a mechanism of MSC action, we show that IL-10 production by nasally administered MSC is critical for reversal of CIPN. In addition, IL-10 signaling via IL-10 receptors expressed by peripheral sensory neurons is crucial for MSC-mediated recovery of CIPN symptoms. We report that nasally administered MSC can be traced in the brain, meninges of the brain and spinal cord meninges. We observed an abundant presence of MSC within 30 min-1 hour after administration in the meninges of the brain, where MSC were still detected up to 7 days later. MSC were also present in the brain and meninges of the spinal cord at 12-24 hours albeit in low numbers. Interestingly, mitochondria derived from MSC were taken up by macrophages in the meninges of the brain which induced macrophages to increase production of IL-10. The latter suggest that the meningeal compartment may ‘educate’ immune cells to a regenerative healing phenotype. Finally, we review the mechanisms and functions of mitochondrial transfer from MSC to damaged neural cells.