Transplantation of hNT neurons into the ischemic cortex: Cell survival and effect on sensorimotor behavior

Abstract

Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory-motor function. hNT-transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors.

Behavioral tests for preclinical intervention assessment

“…The beam can be fitted with a step-down ledge that serves as a "crutch" to prevent full slipping of the limb. 34,35 Rats can be easily encouraged to walk toward a home-cage goal at the end of the beam, or to a dark familiar compartment. During training, the animal is placed on the beam near the goal, and over trials the distance between the goal and the starting place is progressively increased.…”

Two-component protein-engineered physical hydrogels for cell encapsulation

“…Transplantation of many cell types including endothelial cells (36) and adult neural stem cells (37) have produced partial functional recovery in animal models with a wide spectrum of lesions. However, most cell transplantation protocols inject cells suspended in liquid medium, which often results in low viability after implantation (15-35%) and unpredictable outcomes (38)(39)(40). Cell viability directly correlates to functional outcome; therefore, there is a strong need to develop efficient methods of cell delivery (41,42).…”

Neural Stem Cells: Exogenous and Endogenous Promising Therapies for Stroke

“…Site of transplantation may be relevant to cell survival, with pathological evidence of 33.4 ± 6.1% viable cells when human fetal neural stem cells (hNSCs) were transplanted in non-ischemic tissue medial to the ischemic lesion (Kelly et al, 2004). In contrast 30-50% of hNT cells have been suggested to survive in and around the ischemic tissue (Bliss et al, 2006). Inflammation following ischemic stroke may aid cell migration (Belmadani et al, 2006), but a negative correlation between cell survival and inflammatory response has also been observed (Kelly et al, 2004), and may be a factor to consider when timing cell administration.…”