Second-generation reprogramming of somatic cells directly into the cell type of interest avoids induction of pluripotency and subsequent cumbersome differentiation procedures. Several recent studies have reported direct conversion of human somatic cells into stably proliferating induced neural stem cells (iNSCs). Importantly, iNSCs are easier, faster, and more cost-efficient to generate than induced pluripotent stem cells (iPSCs), and also have a higher level of clinical safety. Stably, self-renewing iNSCs can be derived from different cellular sources, such as skin fibroblasts and peripheral blood mononuclear cells, and readily differentiate into neuronal and glial lineages that are indistinguishable from their iPSC-derived counterparts or from NSCs isolated from primary tissues. This review focuses on the derivation and characterization of iNSCs and their biomedical applications. We first outline different approaches to generate iNSCs and then discuss the underlying molecular mechanisms. Finally, we summarize the preclinical validation of iNSCs to highlight that these cells are promising targets for disease modeling, autologous cell therapy, and precision medicine.
Take the shortcut: from iPSC to iNSCForced expression of lineage-specific transcription factors (TFs) has been shown to reprogram the developmental potential of various somatic cell types e.g. by inducing pluripotency [1]. The seminal breakthrough of fibroblast reprogramming into iPSCs offers a novel experimental tool to generate patient-specific cells for developmental studies and diverse biomedical applications, such as disease modeling and cell therapy. Since then, efficiency and robustness of reprogramming protocols have been substantially improved, but the derivation of patient-specific iPSCs remains a lengthy and cumbersome procedure. Moreover, clinical applications require subsequent redifferentiation of iPSCs into the cell type of interest, which is inefficient and risky because transplanted undifferentiated iPSCs are tumorigenic. In the shadow of iPSC-type reprogramming, second-generation reprogramming paradigms have been developed to bypass the pluripotency state Abbreviations