title: Enhancing the efficiency of direct reprogramming of human primary fibroblasts into dopaminergic neuron-like cells through p53 suppression.
abstract: Dopaminergic (DA) neuron-like cells obtained through direct reprogramming of primary human fibroblasts offer exciting opportunities for treatment of Parkinson's disease. A significant obstacle is the low efficiency of conversion during the reprogramming process. Here, we demonstrate that the suppression of p53 significantly enhances the efficiency of transcription factor-mediated conversion of human fibroblasts into functional dopaminergic neurons. In particular, blocking p53 activity using a dominant-negative p53 (p53-DN) in IMR90 cells increases the conversion efficiency by 5-20 fold. The induced DA neuron-like cells exhibit dopamine neuron-specific gene expression, significant dopamine uptake and production capacities, and enables symptomatic relief in a rat Parkinson's disease model. Taken together, our findings suggest that p53 is a critical barrier in direct reprogramming of fibroblast into dopaminergic neurons.
authors.affiliation: Department of Dermatology, Duke University Medical Center, Durham, North Carolina, 27710, USA.
authors.forename: XinJian
authors.initials: X
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Chuan-Yuan
authors.initials: CY
authors.lastname: Li
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000166:cytology*; D010300:Parkinson Disease / Q000628:therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D016159:Tumor Suppressor Protein p53; D004298:Dopamine