Blood-derived stable induced neural stem cells: Preservation of age-related DNA methylation patterns and applicability to disease modeling

Direct transcription factor-mediated cell fate conversion provides an attractive route for the derivation of patient-specific somatic cells. Here we report on the generation of bona fide induced neural stem cells (iNSCs) from adult peripheral blood and their suitability for modeling late-onset disease. Employing restricted and integration-free expression of the transcription factors SOX2 and c-MYC we generated clonally expandable iNSCs that can proliferate across at least 20 passages, remain highly responsive to regional patterning cues and give rise to functional neurons, astrocytes and oligodendrocytes. Interestingly, and in contrast to pluripotent stem cell-derived neural cells, iNSCs exhibit partial preservation of age-related DNA methylation signatures. Employing the polyglutamine disorder Machado-Joseph disease (MJD) as an exemplar, we demonstrate that MJD iNSC-derived neurons show a striking and specific pathological protein aggregation phenotype. Our findings suggest that iNSCs may provide a particularly attractive resource for modeling late-onset neurological disorders.

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