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

• DOI: 10.1038/srep12622
• Publication Date: 2015-07-30T09:14:48Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; Induced Pluripotent Stem Cells; LIM-Homeodomain Proteins; Action Potentials; Mice, Transgenic; Nerve Tissue Proteins; Article; Nestin; Mice; 03 medical and health sciences; Neural Stem Cells; Animals; Cell Lineage; Cells, Cultured; Cell Proliferation; Dopaminergic Neurons; Neurosciences; MPTP Poisoning; Cell Differentiation; Medical Pharmacology; Fibroblasts; Mice, Inbred C57BL; Doxorubicin; Hepatocyte Nuclear Factor 3-beta

AbstractDegeneration 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.