Transplantation of Neuronal and Glial Precursors Dramatically Improves Sensorimotor Function but Not Cognitive Function in the Traumatically Injured Brain

Abstract

Embryonic stem (ES) cells have been investigated in various animal models of neurodegenerative disease; however, few studies have examined the ability of ES cells to improve functional outcome following traumatic brain injury (TBI). The purpose of the present study was to examine the ability of pre-differentiated murine ES cells (neuronal and glial precursors) to improve functional outcome. Rats were prepared with a unilateral controlled cortical impact injury or sham and then transplanted 7 days later with 100K ES cells (WW6G) (~30% neurons) or media. Two days following transplantation rats were tested on a battery of behavioral tests. It was found that transplantation of ES cells improved behavioral outcome by reducing the initial magnitude of the deficit on the bilateral tactile removal and locomotor placing tests. ES cells also induced almost complete recovery on the vibrissae --> forelimb placing test, whereas, media-transplanted rats failed to show recovery. Acquisition of a reference memory task in the Morris water maze was not improved by transplantation of ES cells. Histological analysis revealed a large number of surviving ES cells in the lesion cavity and showed migration of ES cells into subcortical structures. It was found that transplantation of ES cells prevented the occurrence of multiple small necrotic cavities that were seen in the cortex adjacent to the lesion cavity in media transplanted rats. Additionally, ES cells transplants also significantly reduced lesion size. Results of this study suggest that ES cells that have been pre-differentiated into neuronal precursors prior to transplantation have therapeutic potential.

Transplantation of GABAergic neurons but not astrocytes induces recovery of sensorimotor function in the traumatically injured brain

“…Murine ES cells (D3, ATCC) were transfected in the presence of FuGENE 6 (Roche) to express green fluorescent protein (GFP) [10,13,22,23]. Transfected colonies were selected as described previously [13] (see Fig.…”

“…A standard CCI model was used in this experiment that produced a moderate injury [13]. Subjects were anesthetized with a ketamine (90 mg/kg, i.p.)…”

“…GABAergic neurons, astrocytes, stromal cells, or media were transplanted 7 days following injury [13]. Animals were anesthetized with ketamine (90 mg/kg, i.p.)…”

“…This study showed that NSCs survived in the lesion cavity for up to 13 weeks following transplantation and improved motor but not cognitive function. Investigating the capabilities of neuronal and glial precursors in an ES cell transplantation study, we reported that neuronal and glial precursors significantly improved sensorimotor function but not cognitive function following CCI of the sensorimotor cortex (SMC) [13]. Specifically, a mixed culture of neuronal and glial precursors facilitated an initial reduction in the magnitude of behavioral impairments in the bilateral tactile removal and locomotor placing tests, and significantly improved functional improvement on the vibrissae-forelimb placing test.…”

“…Pre-differentiated ES cells have been shown to facilitate motor recovery following TBI [13,24]. However, it is unknown if the observed functional improvement is produced by neuronal or glial cell lineages in the mixed culture.…”