title: Direct induction of neural progenitor cells transiently passes through a partially reprogrammed state.
abstract: The generation of functional neural progenitor cells (NPCs) holds great promise for both research and clinical applications in neurodegenerative diseases. Traditionally, NPCs are derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), or NPCs can be directly converted from somatic cells by sets of transcription factors or by a combination of chemical cocktails and/or hypoxia. However, the ethical issues of ESCs, the risk of tumorigenesis from iPSCs and transgenic integration from exogenous genes as well as complicated manipulation and time-consuming of chemical induced NPCs (ciNPCs) limit the applications of these strategies. Here, we describe a novel method for generating growth factor-induced neural progenitor cells (giNPCs) from mouse embryonic and adult fibroblasts by using inductive and/or permissive signaling culture conditions. These giNPCs closely resemble brain-derived NPCs in terms of transcription networks and neural lineage differentiation potentials. Moreover, this somatic cell to NPC induction is a gradual process that includes initiation, intermediate, maturation and stabilization stages. Importantly, gene expression and histone modification analyses further indicate a partially reprogrammed state during the generation process of induced NPCs, in which lineage specific genes and pluripotency associated genes are transiently activated. Our study therefore describes the potential safety problems that also exist in the transgene-free direct induction strategy and highlights the importance of excluding the possibility of residual partially reprogrammed and/or teratoma-like cells from the generated NPCs for future clinical trials.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, 100084, China; National Institute of Biological Sciences, NIBS, Beijing, 102206, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Xiu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Ruge
authors.initials: R
authors.lastname: Zang
authors.affiliation: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Chenfei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Wang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yi
authors.affiliation: Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Jiajie
authors.initials: J
authors.lastname: Xi
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Liu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Institute for Translational Nanomedicine, Shanghai East Hospital, Institute of Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Shanghai, 200092, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wen
authors.affiliation: Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, 100084, China; National Institute of Biological Sciences, NIBS, Beijing, 102206, China. Electronic address: chenliang@nibs.ac.cn.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. Electronic address: chenjiayu@tongji.edu.cn.
authors.forename: Jiayu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity & Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. Electronic address: gaoshaorong@tongji.edu.cn.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Gao
mesh_terms: D000818:Animals; D061249:Batch Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D000067470:Cellular Reprogramming Techniques / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology* / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D023822:Tissue Engineering / Q000379:methods
keywords: Direct induction; Partially reprogrammed state; giNPCs