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; Lee Mosley, R; Chen, Xiangmei; Huang, Jian; Zheng, Jialin C

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

Afiliación

Tian C; Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.
Li Y; Department of Pharmacology and Experimental Neuroscience.
Huang Y; University of Nebraska Medical Center, Omaha, NE 68198, USA.
Wang Y; Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.
Chen D; Department of Pharmacology and Experimental Neuroscience.
Liu J; University of Nebraska Medical Center, Omaha, NE 68198, USA.
Deng X; Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.
Sun L; Department of Pharmacology and Experimental Neuroscience.
Anderson K; University of Nebraska Medical Center, Omaha, NE 68198, USA.
Qi X; Department of Pharmacology and Experimental Neuroscience.
Li Y; University of Nebraska Medical Center, Omaha, NE 68198, USA.
Lee Mosley R; Department of Nephrology, Chinese PLA General Hospital, Beijing 100853, P. R. China.
Chen X; Department of Emergency Medicine.
Huang J; University of Nebraska Medical Center, Omaha, NE 68198, USA.
Zheng JC; Center for Translational Neurodegeneration and Regenerative Therapy, Shanghai Tenth People's Hospital affiliated to Tongji University School of Medicine, Shanghai 200072, China.

Sci Rep ; 5: 12622, 2015 Jul 30.

Article en En | MEDLINE | ID: mdl-26224135

RESUMEN

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.

Asunto(s)

Neuronas Dopaminérgicas/metabolismo; Fibroblastos/citología; Células-Madre Neurales/metabolismo; Potenciales de Acción/efectos de los fármacos; Animales; Diferenciación Celular; Linaje de la Célula; Proliferación Celular/efectos de los fármacos; Células Cultivadas; Neuronas Dopaminérgicas/citología; Doxorrubicina/toxicidad; Fibroblastos/metabolismo; Factor Nuclear 3-beta del Hepatocito/genética; Factor Nuclear 3-beta del Hepatocito/metabolismo; Células Madre Pluripotentes Inducidas/citología; Células Madre Pluripotentes Inducidas/metabolismo; Células Madre Pluripotentes Inducidas/trasplante; Proteínas con Homeodominio LIM/genética; Proteínas con Homeodominio LIM/metabolismo; Intoxicación por MPTP/terapia; Masculino; Ratones; Ratones Endogámicos C57BL; Ratones Transgénicos; Proteínas del Tejido Nervioso/genética; Proteínas del Tejido Nervioso/metabolismo; Nestina/genética; Nestina/metabolismo; Células-Madre Neurales/citología; Factores de Transcripción Otx/genética; Factores de Transcripción Otx/metabolismo; Factores del Dominio POU/genética; Factores del Dominio POU/metabolismo; Técnicas de Placa-Clamp; Proteínas Proto-Oncogénicas c-myc/genética; Proteínas Proto-Oncogénicas c-myc/metabolismo; Reacción en Cadena en Tiempo Real de la Polimerasa; Factores de Transcripción SOXB1/genética; Factores de Transcripción SOXB1/metabolismo; Serina Endopeptidasas/genética; Serina Endopeptidasas/metabolismo; Factores de Transcripción/genética; Factores de Transcripción/metabolismo

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Células-Madre Neurales / Neuronas Dopaminérgicas / Fibroblastos Idioma: En Revista: Sci Rep Año: 2015 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido

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