Neural Precursor Cell Transplantation Enhances Functional Recovery and Reduces Astrogliosis in Bilateral Compressive/Contusive Cervical Spinal Cord Injury

Abstract

Spinal cord injury has a significant societal and personal impact. Although the majority of injuries involve the cervical spinal cord, few studies of cell transplantation have used clinically relevant models of cervical spinal cord injury, limiting translation into clinical trials. Given this knowledge gap, we sought to examine the effects of neural stem/precursor cell (NPC) transplants in a rodent model of bilateral cervical contusion-compression spinal cord injury. Bilateral C6-level clip contusion-compression injuries were performed in rats, which were then blindly randomized at 2 weeks after injury into groups receiving adult brain-derived NPCs, vehicle, or sham operation. Long-term survival of NPCs was evident at 10 weeks after transplant. Cell grafts were localized rostrocaudally surrounding the lesion, throughout white and gray matter. Graft-derived cells were found within regions of gliotic scar and motor tracts and deposited myelin around endogenous axons. The majority of NPCs developed an oligodendroglial phenotype with greater neuronal profiles in rostral grafts. Following NPC transplantation, white matter was significantly increased compared with control. Astrogliosis and glial scar deposition, measured by GFAP-positive and chondroitin sulfate proteoglycan-positive volume, was significantly reduced. Forelimb grip strength, fine motor control during locomotion, and axonal conduction (by in vivo electrophysiology) was greater in cell-treated animals compared with vehicle controls. Transplantation of NPCs in the bilaterally injured cervical spinal cord results in significantly improved spinal cord tissue and forelimb function, warranting further study in preclinical cervical models to improve this treatment paradigm for clinical translation.

Multimodal Therapeutic Effects of Neural Precursor Cells Derived from Human-Induced Pluripotent Stem Cells through Episomal Plasmid-Based Reprogramming in a Rodent Model of Ischemic Stroke

“…Given the complex functional role of reactive astrocytes, it is unclear whether the finding of glial scar reduction after ep-iPSC-NPC transplantation was beneficial or detrimental for functional recovery in this study. Previous studies have reported that transplanted NPCs reduce glial scar formation and functional recovery as found in our study [11,43,[58][59][60]. One possible explanation is that a reduction in glial scarring is attributable to the indirect effect of transplanted ep-iPSC-NPCs by the amelioration of inflammation.…”

Neuroinflammatory signals enhance the immunomodulatory and neuroprotective properties of multipotent adult progenitor cells

“…Stem cell transplantation represents a promising therapeutic approach to treat neuroinflammatory and neurodegenerative disorders. By using experimental murine models of neuroinflammatoy diseases, such as experimental autoimmune encephalomyelitis (EAE), traumatic brain injury (TBI) and spinal cord injury (SCI), several studies demonstrated that stem cells reduce neurological deterioration and protect the central nervous system (CNS) from further damage and even stimulate its repair [ 1 – 7 ]. In these studies both adult-derived bone marrow mesenchymal stem cells (MSCs) and newborn CNS-derived neural stem cells (NSCs) provided neurotrophic support and even replaced damaged oligodendrocytes and neurons [ 3 – 5 ].…”

Does the preclinical evidence for functional remyelination following myelinating cell engraftment into the injured spinal cord support progression to clinical trials?

“…Immuno-electron microscopy (EM) remains the best method to verify remyelination of host axons with engrafted cells. Only 20% of these studies provided evidence of exogenous remyelination via immune-EM, although five studies used confocal microscopy to identify close apposition of oligodendrocyte marker-expressing, fluorescent protein expressing-engrafted cells to host neurofilament-expressing axons (Hawryluk et al, 2014; Hu et al, 2013; Karimi-Abdolrezaee et al, 2010; Plemel et al, 2011; Wilcox et al, 2014). The ability of grafted cells to simply differentiate into oligodendrocytes with the potential to remyelinate was investigated using immunohistochemical staining against markers for mature oligodendrocytes (i.e.…”