The study investigates the reprogramming of brain-derived neural stem (NS) cells to induced pluripotent stem (iPS) cells using genetic manipulation. NS cells, which are less restricted by epigenetic factors compared to other somatic cells, were found to rapidly and efficiently acquire an undifferentiated morphology after transduction with reprogramming factors. However, these cells did not fully attain true pluripotency, lacking stable expression of endogenous Oct4 and Nanog, epigenetic erasure of X chromosome silencing, and the ability to form chimaeras. To address this, the authors applied molecularly defined conditions for the derivation and propagation of authentic pluripotent stem cells from embryos, combining dual inhibition (2i) of mitogen-activated protein kinase signaling and glycogen synthase kinase-3 (GSK3) with the self-renewal cytokine leukemia inhibitory factor (LIF). This treatment induced stable up-regulation of Oct4 and Nanog, reactivation of the X chromosome, transgene silencing, and competence for somatic and germline chimaerism. Using 2i/LIF, NS cell reprogramming required only 1-2 integrations of each transgene, and transduction with Sox2 and c-Myc was dispensable, with Oct4 and Klf4 sufficient to convert NS cells into chimaera-forming iPS cells. These findings demonstrate that somatic cell state influences reprogramming requirements and outline two phases in the reprogramming process, highlighting the potential for molecular dissection of this phenomenon.The study investigates the reprogramming of brain-derived neural stem (NS) cells to induced pluripotent stem (iPS) cells using genetic manipulation. NS cells, which are less restricted by epigenetic factors compared to other somatic cells, were found to rapidly and efficiently acquire an undifferentiated morphology after transduction with reprogramming factors. However, these cells did not fully attain true pluripotency, lacking stable expression of endogenous Oct4 and Nanog, epigenetic erasure of X chromosome silencing, and the ability to form chimaeras. To address this, the authors applied molecularly defined conditions for the derivation and propagation of authentic pluripotent stem cells from embryos, combining dual inhibition (2i) of mitogen-activated protein kinase signaling and glycogen synthase kinase-3 (GSK3) with the self-renewal cytokine leukemia inhibitory factor (LIF). This treatment induced stable up-regulation of Oct4 and Nanog, reactivation of the X chromosome, transgene silencing, and competence for somatic and germline chimaerism. Using 2i/LIF, NS cell reprogramming required only 1-2 integrations of each transgene, and transduction with Sox2 and c-Myc was dispensable, with Oct4 and Klf4 sufficient to convert NS cells into chimaera-forming iPS cells. These findings demonstrate that somatic cell state influences reprogramming requirements and outline two phases in the reprogramming process, highlighting the potential for molecular dissection of this phenomenon.