Long-term benefit of human fetal neuronal progenitor cell transplantation in a clinically adapted model after traumatic brain injury

Experimental human fetal neural progenitor cell (hfNPC) transplantation has proven to be a promising therapeutic approach after traumatic brain injury (TBI). However the long-term efficacy and safety, which are both highly important for clinical translation of this approach, have not been investigated so far. This study investigated the effect of local (1x105 cells) (L) and systemic (5x105 cells) (S) administration of PKH-26-labeled pre-differentiated hfNPCs over a period of twelve weeks, twenty-four hours after severe controlled cortical impact TBI in Sprague-Dawley rats. Accelerating rotarod testing revealed a trend of functional improvement beginning one week after transplantation and persisting until the end of the experiment. The traumatic lesion volume as quantified by magnetic resonance imaging was smaller in both treatment groups when compared to control (C) animals (C = 54.50 mm3, L = 32 mm3, S = 37.50 mm3). Correspondingly, NeuN staining showed increased neuronal survival at the border of the lesion in both transplanted groups (S: 92.4%; L: 87.2%; 72.5%). Histological analysis of brain compartments revealed transiently increased angiogenesis and reduced astroglial reaction during the first four weeks post-transplantation. PKH-26-positive cells were detected exclusively after local transplantation without any evidence of tumor formation. However, graft differentiation was only observed in very rare cases. In conclusion, transplantation of hfNPCs improved the long-term functional outcome after TBI, diminished trauma lesion size and increased neuronal survival in the border zone of the lesion. This therapeutic effect was most unlikely due to cell replacement but was associated with transiently increased angiogenesis and reduced astrogliosis