Intravenous Infusion of Mesenchymal Stem Cells Alters Motor Cortex Gene Expression in a Rat Model of Acute Spinal Cord Injury

Abstract

Recent evidence has demonstrated that remote responses in the brain, as well as local responses in the injured spinal cord, can be induced after spinal cord injury (SCI). Intravenous infusion of mesenchymal stem cells (MSCs) has been shown to provide functional improvements in SCI through local therapeutic mechanisms that provide neuroprotection, stabilization of the blood-spinal cord barrier, remyelination, and axonal sprouting. In the present study, we examined the brain response that might be associated with the functional improvements induced by the infused MSCs after SCI. Genome-wide RNA profiling was performed in the motor cortex of SCI rats at 3 days post-MSC or vehicle infusion. Then, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) data revealed that the "behaviorally-associated differentially expressed genes (DEGs)" were identified by the Pearson's correlation analysis with the behavioral function, suggesting that the "behaviorally-associated DEGs" may be related to the functional recovery after systemic infusion of MSCs in SCI. These results suggested that the infused MSCs alter the gene expression signature in the brain and that these expression changes may contribute to the improved function in SCI.

Intravenous Infusion of Autoserum-Expanded Autologous Mesenchymal Stem Cells in Patients With Chronic Brain Injury: Protocol for a Phase 2 Trial

“…Since brain injuries in the chronic phase are heterogenous injuries that are underpinned by numerous complex and interrelated pathophysiological conditions [ 35 ], it is conceivable that the enhanced neural plasticity resulting from MSC injection promotes structural rewiring, which might contribute to functional improvement in chronic state of neural diseases. In addition, there are other multimodal and orchestrated mechanisms, as shown in previous studies [ 3 - 13 , 15 - 18 , 25 , 28 , 32 - 34 , 36 - 38 ]. Given these considerations of the potential therapeutic effects of MSCs in a number of neurological disorders, we planned a clinical trial for chronic brain injury.…”

“…The intravenous infusion of MSCs derived from bone marrow improves functional outcomes in experimental animal models of stroke [ 4 - 7 , 9 - 11 ], SCI [ 13 , 14 , 16 , 24 , 30 , 31 ], neonatal hypoxic ischemia [ 12 ], chronic epilepsy [ 17 ], cerebral small vessel disease [ 8 , 32 ], amyotrophic lateral sclerosis [ 33 , 34 ], and peripheral nerve injury [ 18 , 21 ]. Although the mechanisms underlying these beneficial effects have not been fully elucidated, potential mechanisms include neuroprotection and immunomodulation [ 14 ], the induction of axonal sprouting [ 13 ], remyelination [ 13 ], the restoration of the blood-brain and blood–spinal cord barriers [ 13 , 24 ], and the enhancement of remote gene expression responses [ 15 ].…”

“…The intravenous infusion of mesenchymal stem cells (MSCs) has shown therapeutic efficacy in experimental animal models of neurological diseases and injuries, including cerebral ischemia [ 3 - 12 ], spinal cord injury (SCI) [ 13 - 16 ], chronic epilepsy [ 17 ], and peripheral nerve injury [ 18 - 20 ]. The suggested therapeutic mechanisms of MSCs from animal studies include the secretion of neurotrophic factors that can provide neuroprotection [ 14 , 17 , 21 ], neovascularization [ 22 , 23 ], the restoration of the blood-brain barrier [ 13 , 24 ], the regeneration of axonal injury [ 13 , 25 ], remyelination [ 13 ], synaptogenesis [ 12 , 25 ], induced neural plasticity [ 12 , 25 ], and remote effects [ 15 ]. These therapeutic mechanisms may have beneficial effects on chronic brain injury as well.…”

SDF-1/CXCR4 Axis-mediated Migration of Systematically Transplanted Bone Marrow Mesenchymal Stem Cells Towards the Injured Spinal Cord in a Rat Model

“…Less invasive techniques suited for the clinical application need to be developed. Trials by intravenous injections of MSCs in rodents were widely reported [44][45][46][47][48]. Cultured rat and human MSCs have been shown to migrate into sites of brain injury after cerebral ischemia when transplanted intravenously in rats [49].…”

“…No previously reported study has tracked MSCs that were intravenously transplanted into the spinal cord in living animals; to date, only histological assessments have con rmed the fate of stem cells after their systemic transplantation [27,[44][45][46][47][48]. These studies did not evaluate the survival, proliferation, and migration of transplanted cells.…”