Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion

Changhai Tian, Yuju Li, Yunlong Huang, Yongxiang Wang, Dapeng Chen, Jinxu Liu, Xiaobei Deng, Lijun Sun, Kristi Anderson, Xinrui Qi, Yulong Li, R Lee Mosley, Xiangmei Chen, Jian Huang, Jialin C Zheng

Research output: Contribution to journalArticle

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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 astroctyes 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.

Original languageEnglish (US)
Article number12622
JournalScientific reports
Volume5
DOIs
StatePublished - Jul 30 2015

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Fibroblasts
Transplantation
Dopaminergic Neurons
Mesencephalon
Parkinson Disease
Corpus Striatum
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Neurogenesis
Neuroglia
Neoplasms
Brain
Genes
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion. / Tian, Changhai; Li, Yuju; Huang, Yunlong; Wang, Yongxiang; Chen, Dapeng; Liu, Jinxu; Deng, Xiaobei; Sun, Lijun; Anderson, Kristi; Qi, Xinrui; Li, Yulong; Mosley, R Lee; Chen, Xiangmei; Huang, Jian; Zheng, Jialin C.

In: Scientific reports, Vol. 5, 12622, 30.07.2015.

Research output: Contribution to journalArticle

Tian, Changhai ; Li, Yuju ; Huang, Yunlong ; Wang, Yongxiang ; Chen, Dapeng ; Liu, Jinxu ; Deng, Xiaobei ; Sun, Lijun ; Anderson, Kristi ; Qi, Xinrui ; Li, Yulong ; Mosley, R Lee ; Chen, Xiangmei ; Huang, Jian ; Zheng, Jialin C. / Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion. In: Scientific reports. 2015 ; Vol. 5.
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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 astroctyes 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.",
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AU - Liu, Jinxu

AU - Deng, Xiaobei

AU - Sun, Lijun

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AU - Qi, Xinrui

AU - Li, Yulong

AU - Mosley, R Lee

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AU - Huang, Jian

AU - Zheng, Jialin C

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