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The potential for directed differentiation of human-induced pluripotent stem (iPS) cells to functional postmitotic neuronal phenotypes is unknown. Following methods shown to be effective at generating motor neurons from human embryonic stem cells (hESCs), we found that once specified to a neural lineage, human iPS cells could be differentiated to form motor neurons with a similar efficiency as hESCs. Human iPS-derived cells appeared to follow a normal developmental progression associated with motor neuron formation and possessed prototypical electrophysiological properties. This is the first demonstration that human iPS-derived cells are able to generate electrically active motor neurons. These findings demonstrate the feasibility of using iPS-derived motor neuron progenitors and motor neurons in regenerative medicine applications and in vitro modeling of motor neuron diseases. Disclosure of potential conflicts of interest is found at the end of this article.

In a comparison of gene expression by A2B5-defined glial tumor progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain (Cell Reports 3:2127-41, 2013), we found that the F2R gene encoding PAR1 was differentially over-expressed by TPCs isolated from primary gliomas at every stage of glioma progression. In this study, we therefore asked if PAR1 activation was causally associated with glioma progression. Lentiviral shRNAi knock-down of PAR1 inhibited the expansion and proliferation of glioma TPCs in vitro. We further found that the PAR-1 receptor antagonists SCH79797 and SCH530348 (vorapaxar) inhibited A2B5+ TPC expansion and migration in vitro. PAR1 knockdown also suppressed the tumorigenic potential of A2B5+ TPCs after transplantation into the brains of immunodeficient mice. In addition, mice given subcutaneous grafts of A2B5+ human glioma TPCs exhibited delayed tumor growth if treated with Vorapaxar, relative to xenografted control mice treated with only vehicle. Together, these data suggest that PAR1 may contribute to glioma progenitor expansion and tumor growth; as such, the abrogation of PAR1 signaling may contribute to the treatment of malignant glioma.