Transplantation of Neural Stem Cells Clonally Derived from Embryonic Stem Cells Promotes Recovery After Murine Spinal Cord Injury

Abstract

The pathology of spinal cord injury (SCI) makes it appropriate for cell-based therapies. Treatments using neural stem cells (NSCs) in animal models of SCI have shown positive outcomes, although uncertainty remains regarding the optimal cell source. Pluripotent cell sources such as embryonic stem cells (ESCs) provide a limitless supply of therapeutic cells. NSCs derived using embryoid bodies (EB) from ESCs have shown tumorigenic potential. Clonal neurosphere generation is an alternative method to generate safer and more clinically relevant NSCs without the use of an EB stage for use in cell-based therapies. We generated clonally derived definitive NSCs (dNSCs) from ESC. These cells were transplanted into a mouse thoracic SCI model. Embryonic stem cell-derived definitive neural stem cell (ES-dNSC)-transplanted mice were compared with controls using behavioral measures and histopathological analysis of tissue. In addition, the role of remyelination in injury recovery was investigated using transmission electron microscopy. The SCI group that received ES-dNSC transplantation showed significant improvements in locomotor function compared with controls in open field and gait analysis. The cell treatment group had a significant enhancement of spared neural tissue. Immunohistological assessments showed that dNSCs differentiated primarily to oligodendrocytes. These cells were shown to express myelin basic protein, associate with axons, and support nodal architecture as well as display proper compact, multilayer myelination in electron microscopic analysis. This study provides strong evidence that dNSCs clonally derived from pluripotent cells using the default pathway of neuralization improve motor function after SCI and enhance sparing of neural tissue, while remaining safe and clinically relevant.

Anti-inflammatory effect of stem cells against spinal cord injury via regulating macrophage polarization

“…Transplantation of NS/PCs is promising treatment for SCI. [99][100][101][102][103] NS/PCs usual has been studied as a mean to replace the damaged neurons in SCI. However, increasing data showed that NSCs can promote motor functional recovery by modulating the host environment.…”

Transplantation of Induced Pluripotent Stem Cell-Derived Neural Stem Cells Mediate Functional Recovery Following Thoracic Spinal Cord Injury Through Remyelination of Axons

“…Clip-compression spinal cord injuries at the T6 level in mice were performed similarly to previously described techniques [19]. In brief, a T5-T7 laminectomy was performed, allowing for the passage of a modified aneurysm clip (FEJOTA mouse clip) at T6.…”

“…The NSC transplantations were performed as previously described [19]. Immune suppression using cyclosporine A (20 mg/kg) began 2 days before transplantation and continued for the duration of the experiment.…”

“…NSCs generated from fetal or embryonic stem cell (ESC) sources have also been used successfully following SCI [9,18,19]. However, concerns related to availability and/or immune compatibility could limit their translational potential.…”

Progress in the study of stem cell transplantation for the repair of spinal cord injury

“…Recent studies have shown that the use of NSCs clonally derived from ESCs for spinal cord injury repair provide much better results than does traditional ESC transplantation. However, current studies have indicated that the prospect of clinical application of ESCs is not optimistic because of the following reasons: 1) the research subjects for spinal cord injury repair using ESC transplantation are limited to rodents, and there are no reports in primate animal models; therefore, it is difficult to evaluate the safety and effectiveness of the procedure for humans; 2) the mechanism of ESC proliferation and differentiation requires further study, and ESC differentiation are affected by local microenvironments, which might be significantly altered after spinal cord injury compared with the microenvironment of a normal body; therefore, directed differentiation is difficult to achieve; 3) there is a risk of forming teratomas after ESC implantation; and 4) there are ethical constraints [22].…”