Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons

Citations Over TimeTop 10% of 2015 papers

Abstract

The direct conversion of fibroblasts to induced dopaminergic (iDA) neurons and other cell types demonstrates the plasticity of cell fate. The low efficiency of these relatively fast conversions suggests that kinetic barriers exist to safeguard cell-type identity. Here we show that suppression of p53, in conjunction with cell cycle arrest at G1 and appropriate extracellular environment, markedly increase the efficiency in the transdifferentiation of human fibroblasts to iDA neurons by Ascl1, Nurr1, Lmx1a and miR124. The conversion is dependent on Tet1, as G1 arrest, p53 knockdown or expression of the reprogramming factors induces Tet1 synergistically. Tet1 knockdown abolishes the transdifferentiation while its overexpression enhances the conversion. The iDA neurons express markers for midbrain DA neurons and have active dopaminergic transmission. Our results suggest that overcoming these kinetic barriers may enable highly efficient epigenetic reprogramming in general and will generate patient-specific midbrain DA neurons for Parkinson's disease research and therapy.

Related Papers

• → Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration(2011)716 cited
• → Progress in the Reprogramming of Somatic Cells(2013)118 cited
• → Chemical reprogramming and transdifferentiation(2017)97 cited
• → Direct reprogramming with SOX factors: masters of cell fate(2017)84 cited
• → Chemical-Mediated Somatic Cell Reprogramming and Transdifferentiation(2018)