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Until now only a few cell lines have been proved able to propagate prions and only limited prion strains have been replicated in cell models. Neurosphere lines isolated from the brains of mice at embryonic day 14 grow as aggregates and contain CNS stem cells. Others authors have previously reported that cultured neurospheres expressing cellular prion protein (PrPC) can be infected with prions. As potential neural progenitors the neurosphere cultures are supposed to differentiate into neurons and astrocytes which represent the main cell types infected by prions in vivo. Here we study the ability of undifferentiated and differentiated neurospheres to replicate several prion strains. Neurosphere cultures were isolated from 129/ola, FVB, Prnp0/0 and Tga20 mice, which over-express murine PrP. We were not able to detect PrPres accumulation in dividing neurosphere cultures after prion exposure to two different mouse adapted scrapie inocula (RML and 22L). In contrast, with differentiated neurosphere cultures expressing PrPC (129/ola, FVB and Tga20) a successful PrPRes amplification was observed in very short time experiments when infected with the same inocula, implying that cell differentiation improve prion replication in these cultured cells. The mouse BSE adapted inocula (301C) was not amplified in these neurosphere cultures neither before nor after differentiation, suggesting that these cell cultures showed a differential prion strain susceptibility. These results suggest that differentiated neurosphere cultures can complement prion bioassays in mouse models. © 2010 Elsevier B.V.