title: Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion.
abstract: Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson's disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state, and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits, and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astrocytes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment.
authors.affiliation: Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.|Department of Pharmacology and Experimental Neuroscience.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Changhai
authors.initials: C
authors.lastname: Tian
authors.affiliation: Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.|Department of Pharmacology and Experimental Neuroscience.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yuju
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.|Department of Pharmacology and Experimental Neuroscience.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Experimental Neuroscience.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Beijing 100853, P. R. China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Emergency Medicine.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Jinxu
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of Pathology and Microbiology.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Experimental Neuroscience.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Anderson
authors.affiliation: Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Emergency Medicine.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Experimental Neuroscience.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lee Mosley
authors.affiliation: Department of Nephrology, Chinese PLA General Hospital, Beijing 100853, P. R. China.
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Chinese National Human Genome Center at Shanghai, Shanghai 201203, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.|Department of Pharmacology and Experimental Neuroscience.|Department of Pathology and Microbiology.|University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Jialin C
authors.initials: JC
authors.lastname: Zheng
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism; D050809:POU Domain Factors / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C496503:Foxa2 protein, mouse; D060850:LIM-Homeodomain Proteins; C489692:Lmx1a protein, mouse; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D050809:POU Domain Factors; D016271:Proto-Oncogene Proteins c-myc; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; C074066:Pou3f2 protein, mouse; D004317:Doxorubicin; C485617:Corin protein, mouse; D012697:Serine Endopeptidases