Cell therapy of stroke in small and large animals

Background and aims: Human umbilical cord blood (HUCB) and bone marrow (BM) stem cells as a stroke treatment is a recent scientific topic. However, little is known about the cellular mechanisms leading to neurofunctional improvement. We evaluated the necessity of CD34+ cells among the transplant and the time window of HUCB cell administration. A comparison between adult vs. fetal neural stem cells (NSC) and local vs. systemic administration was performed. Finally, efficacy of autologous BM transplantation was studied in a novel sheep model. Methods: 139 male rats were assigned to groups as given in figure 1. Stroke was induced by middle cerebral artery occlusion (MCAO). 106 cells were administered intravenously or 3x105 cells were injected locally (striatum). Behavioural outcome was observed until day 29 using common tests (RotaRod, Beamwalk). MRI was performed at days 1, 8 and 29 followed by immunohistochemistry. 19 Merino rams were assigned either to a cell therapy (n =8) or control group (n=11). Cell therapy group received 4x106 autologous mononuclear BM cells per kilogram bodyweight 24 hours upon MCAO. Behavioural phenotyping and MRI were performed until day. Results: Surprisingly, CD34- and CD34+ samples had nearly the same therapeutic effect. HUCB and BM derived cells were detected in the border zone of the lesion. Cell treatment was superior to saline injection (p<0.01). T-cell transplantation and HUCB cell treatment after 14 days failed to induce functional improvement. T-cell administration was even inferior as compared to controls (p<0.05). Local administration did not show superiority. Neural differentiation was only observed upon local NSC administration while reduction of gliosis/lesion size and neurofunctional improvement were observed in all groups receiving sufficient cell treatment, also in the large animal arm. Conclusion: Results are consistent with the hypothesis that HUCB cells, BM cells and NSCs provide an excellent cell-based treatment for st