Enhanced Network in Corticospinal Tracts after Infused Mesenchymal Stem Cells in Spinal Cord Injury

Abstract

Although limited spontaneous recovery occurs after spinal cord injury (SCI), current knowledge reveals that multiple forms of axon growth in spared axons can lead to circuit reorganization and a detour or relay pathways. This hypothesis has been derived mainly from studies of the corticospinal tract (CST), which is the primary descending motor pathway in mammals. The major CST is the dorsal CST (dCST), being the major projection from cortex to spinal cord. Two other components often called “minor” pathways are the ventral and the dorsal lateral CSTs, which may play an important role in spontaneous recovery. Intravenous infusion of mesenchymal stem cells (MSCs) provides functional improvement after SCI with an enhancement of axonal sprouting of CSTs. Detailed morphological changes of CST pathways, however, have not been fully elucidated. The primary objective was to evaluate detailed changes in descending CST projections in SCI after MSC infusion. The MSCs were infused intravenously one day after SCI. A combination of adeno-associated viral vector (AAV), which is an anterograde and non-transsynaptic axonal tracer, was injected 14 days after SCI induction. The AAV with advanced tissue clearing techniques were used to visualize the distribution pattern and high-resolution features of the individual axons coursing from above to below the lesion. The results demonstrated increased observable axonal connections between the dCST and axons in the lateral funiculus, both rostral and caudal to the lesion core, and an increase in observable axons in the dCST below the lesion. This increased axonal network could contribute to functional recovery by providing greater input to the spinal cord below the lesion.

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

“…We previously reported on the safety, feasibility, and potential therapeutic efficacy of the intravenous infusion of autoserum-expanded autologous MSCs for patients with cerebral infarction [ 27 ] and subacute SCI [ 28 ]. 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 ].…”

Mesenchymal Stem Cell Transplantation for Spinal Cord Injury: Current Status and Prospects

“…We previously reported that the intravenous infusion of MSCs improved functional outcomes in experimental SCI models 7,8,10,11 . Cellular therapy using Spine Surgery and Related Research J-STAGE Advance Publication (February 13, 2023) Ⓒ The Japanese Society for Spine Surgery and Related Research.…”

“…Experimental research in regenerative medicine on spinal repair has helped in developing new therapies using various types of cells as donor cells. The donor cells reported on so far include Schwann cells 3 , olfactory ensheathing cells 4 , embryonic stem cells 5 , neural stem cells/neural precursor cells 6 , mesenchymal stem cells (MSCs) [7][8][9][10][11] , and induced pluripotent stem cells 12 . Among these, bone marrow-derived MCSs are considered the most promising and feasible cell source for cellular therapy.…”

“…Among these, bone marrow-derived MCSs are considered the most promising and feasible cell source for cellular therapy. Notably, intravenous administration has been found to have favorable therapeutic effects on neurological diseases 13 , including SCI [7][8][9][10][11] .…”