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.

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Motor control and learning impairments are common complications in individuals with autism spectrum disorder (ASD). Abnormal cerebellar development during critical phases may disrupt these motor functions and lead to autistic motor dysfunction. However, the underlying mechanisms behind these impairments are not clear. Here, we utilized BTBR T + Itpr tf /J (BTBR) mice, an animal model of autism, to investigate the involvement of abnormal cerebellar development in motor performance. We found BTBR mice exhibited severe dystonia-like behavior and motor coordination or motor learning impairments. The onset of these abnormal movements coincided with the increased proliferation of granule neurons and enhanced foliation, and Purkinje cells displayed morphological hypotrophy with increased dendritic spine formation but suppressed maturation. The migration of granule neurons seemed unaffected. Transcriptional analyses confirmed the differential expression of genes involved in abnormal neurogenesis and revealed TRPC as a critical regulator in proliferation and synaptic formation. Taken together, these findings indicate that abnormal cerebellar development is closely related to dystonia-like behavior and motor dysfunction of BTBR mice and that TRPC may be a novel risk gene for ASD that may participate in the pathological process of autistic movement disorders.

Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interactions and communication and stereotypical patterns of behaviors, interests, or activities. Even with the increased prevalence of ASD, there is no defined standard drug treatment for ASD patients. Currently, stem cells, including human amniotic epithelial cell (hAEC) transplantation, seem to be a promising treatment for ASD, but the effectiveness needs to be verified, and the mechanism has not been clarified. Methods We intraventricularly transplanted hAECs into a 2-month-old BTBR T+tf/J (BTBR) mouse model of ASD. Behavior tests were detected 1 month later; hippocampal neurogenesis, neuroprogenitor cell (NPC) pool, and microglia activation were analyzed with immunohistochemistry and immunofluorescence; the levels of pro-inflammatory cytokines, brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus were determined by real-time PCR or western blotting. Results After intraventricular injection of hAECs into adult males, social deficits in BTBR mice were significantly ameliorated. In addition, hAEC transplantation restored the decline of neurogenesis and NPCs in the hippocampus of BTBR mice by expanding the stem cell pool, and the decreased levels of BDNF and TrkB were also rescued in the hippocampus of the hAEC-injected BTBR mice. Meanwhile, the transplantation of hAECs did not induce microglial overactivation or excessive production of pro-inflammatory cytokines in the hippocampus of BTBR mice. Conclusions Based on these results, we found that hAEC transplantation ameliorated social deficits and promoted hippocampal neurogenesis in BTBR mice. Our study indicates a promising therapeutic option that could be applied to ASD patients in the future.