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Direct reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a

Dongchang Xiao,Xiaoning Liu,Min Zhang,Min Zou,Qinqin Deng,Dayu Sun,Xuting Bian,Yulong Cai,Yanan Guo,Shuting Liu,Shengguo Li,Evelyn Shiang,Hongyu Zhong,Lin Cheng,Haiwei Xu,Kangxin Jin,M. Xiang

Published 2018 in Nature Communications

ABSTRACT

Induced neural stem cells (iNSCs) reprogrammed from somatic cells have great potentials in cell replacement therapies and in vitro modeling of neural diseases. Direct conversion of fibroblasts into iNSCs has been shown to depend on a couple of key neural progenitor transcription factors (TFs), raising the question of whether such direct reprogramming can be achieved by non-neural progenitor TFs. Here we report that the non-neural progenitor TF Ptf1a alone is sufficient to directly reprogram mouse and human fibroblasts into self-renewable iNSCs capable of differentiating into functional neurons, astrocytes and oligodendrocytes, and improving cognitive dysfunction of Alzheimer’s disease mouse models when transplanted. The reprogramming activity of Ptf1a depends on its Notch-independent interaction with Rbpj which leads to subsequent activation of expression of TF genes and Notch signaling required for NSC specification, self-renewal, and homeostasis. Together, our data identify a non-canonical and safer approach to establish iNSCs for research and therapeutic purposes. Fibroblasts can be reprogrammed into induced neural stem cells (iNSCs) using transcription factors expressed in neural progenitors. Here the authors show that Ptf1a, which is normally expressed in postmitotic neurons, can reprogram fibroblasts to iNSCs through Notch independent interaction with Rbpj.

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