Human induced neural progenitor cells reinforce the local neural circuits and improve cognitive abilities in a mouse model of Alzheimer's Disease Ting Zhang1,6, Chunmei Yue1,6, Wei Ke2, Xuan Zhou3, Yun Qian1, Yanhong Duan3, Su Feng1, Ran Wang1, Guizhong Cui1, Ran Tao1, Wenke Guo1,5, Xiaobing Zhang4, Xiaohua Cao3, Yousheng Shu2, Naihe Jing1, 5* 1State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, 200031, China; 2State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, 19 Xinjiekou Wai Street, Beijing, 100875, China; 3Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Sciences, East China Normal University, Shanghai, China; 4Division of Regenerative Medicine, Department of Medicine, Loma Linda University, CA, 92350, USA; 5School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China 6Co-first authors *Corresponding Author
Great efforts have been made to convert human fibroblasts into induced neural stem/progenitor cells (iNPCs) that is assumed to have invaluable potential in cell replacement therapies. However, the therapeutic potential of human iNPCs remains unevaluated. Here, immobilized human peripheral blood cells were converted into non-integrated iNPCs that display self-renewing capacity, transcriptome profile and multipotent properties resembling NPCs in the brain. After transplantation into the hippocampus of immunodeficient mice, human iNPCs efficiently differentiated into neurons that possessed neuronal membrane properties, gradually matured, formed synaptic graft-host connections with mouse neurons and functionally integrated into the local neural circuits. Moreover, immunodeficient mice modelling Alzheimer's Disease (AD) exhibited improved cognitive ability and enhanced hippocampal LTP upon hippocampal transplantation of human iNPCs. Collectively, our results demonstrate that the functional integration of grafted human iNPCs partially reinforces endogenous neural circuits, enhances synaptic plasticity and eventually ameliorates the cognitive deficits of AD mice, suggesting that human iNPCs might serve as a promising therapeutic tool to restore function in the AD brain.
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