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

doi:10.1038/srep12622

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

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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 language	English
Article number	12622
Journal	Scientific Reports
Volume	5
DOIs	https://doi.org/10.1038/srep12622
State	Published - Jul 30 2015

Bibliographical note

Funding Information:
We would like to thank Drs. Yong Zhao, Shaorong Gao, Terry Hexum for valuable suggestions and discussions and Yi Wang, Beiqing Wu, Runze Zhao, Miao He and Dr. You Zhou for technical supports. This work was partly supported by research grants by National Basic Research Program of China (973 Program Grant No. 2014CB965001), National Natural Science Foundation of China (#81271419), Innovative Research Groups of the National Natural Science Foundation of China (#81221001), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (#81329002); National Institutes of Health: R01 NS 41858-01, R01 NS 061642-01, P20 RR15635-01, the State of Nebraska, DHHS-LB606 Stem Cell 2009-10 (JZ), LB606 Stem Cell-2010-10 (CT). Julie Ditter, Lenal Bottoms, Jaclyn Ostronic, Johna Belling, and Robin Taylor provided outstanding administrative and secretarial support.

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@article{d5879caf4e26407598c28da8ed1a7718,

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 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.",

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

note = "Funding Information: We would like to thank Drs. Yong Zhao, Shaorong Gao, Terry Hexum for valuable suggestions and discussions and Yi Wang, Beiqing Wu, Runze Zhao, Miao He and Dr. You Zhou for technical supports. This work was partly supported by research grants by National Basic Research Program of China (973 Program Grant No. 2014CB965001), National Natural Science Foundation of China (#81271419), Innovative Research Groups of the National Natural Science Foundation of China (#81221001), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (#81329002); National Institutes of Health: R01 NS 41858-01, R01 NS 061642-01, P20 RR15635-01, the State of Nebraska, DHHS-LB606 Stem Cell 2009-10 (JZ), LB606 Stem Cell-2010-10 (CT). Julie Ditter, Lenal Bottoms, Jaclyn Ostronic, Johna Belling, and Robin Taylor provided outstanding administrative and secretarial support.",

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doi = "10.1038/srep12622",

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T1 - Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion

AU - Tian, Changhai

AU - Li, Yuju

AU - Huang, Yunlong

AU - Wang, Yongxiang

AU - Chen, Dapeng

AU - Liu, Jinxu

AU - Deng, Xiaobei

AU - Sun, Lijun

AU - Anderson, Kristi

AU - Qi, Xinrui

AU - Li, Yulong

AU - Lee Mosley, R.

AU - Chen, Xiangmei

AU - Huang, Jian

AU - Zheng, Jialin C.

N1 - Funding Information: We would like to thank Drs. Yong Zhao, Shaorong Gao, Terry Hexum for valuable suggestions and discussions and Yi Wang, Beiqing Wu, Runze Zhao, Miao He and Dr. You Zhou for technical supports. This work was partly supported by research grants by National Basic Research Program of China (973 Program Grant No. 2014CB965001), National Natural Science Foundation of China (#81271419), Innovative Research Groups of the National Natural Science Foundation of China (#81221001), and Joint Research Fund for Overseas Chinese, Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China (#81329002); National Institutes of Health: R01 NS 41858-01, R01 NS 061642-01, P20 RR15635-01, the State of Nebraska, DHHS-LB606 Stem Cell 2009-10 (JZ), LB606 Stem Cell-2010-10 (CT). Julie Ditter, Lenal Bottoms, Jaclyn Ostronic, Johna Belling, and Robin Taylor provided outstanding administrative and secretarial support.

PY - 2015/7/30

Y1 - 2015/7/30

N2 - 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.

AB - 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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U2 - 10.1038/srep12622

DO - 10.1038/srep12622

M3 - Article

C2 - 26224135

AN - SCOPUS:84938314368

SN - 2045-2322

VL - 5

JO - Scientific Reports

JF - Scientific Reports

M1 - 12622

ER -

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

Abstract

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