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

Houbo Jiang, Zhimin Xu, Ping Zhong, Yong Ren, Gaoyang Liang, Haley A. Schilling, Zihua Hu, Yi Zhang, Xiaomin Wang, Shengdi Chen, Zhen Yan and Jian Feng ()
Additional contact information
Houbo Jiang: Veterans Affairs Western New York Healthcare System
Zhimin Xu: State University of New York at Buffalo
Ping Zhong: Veterans Affairs Western New York Healthcare System
Yong Ren: State University of New York at Buffalo
Gaoyang Liang: Howard Hughes Medical Institute, Harvard Medical School
Haley A. Schilling: State University of New York at Buffalo
Zihua Hu: Center for Computational Research, New York State Center of Excellence in Bioinformatics & Life Sciences, State University of New York at Buffalo
Yi Zhang: Howard Hughes Medical Institute, Harvard Medical School
Xiaomin Wang: Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing Institute for Brain Disorders, Capital Medical University
Shengdi Chen: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Zhen Yan: Veterans Affairs Western New York Healthcare System
Jian Feng: Veterans Affairs Western New York Healthcare System

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms10100 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10100

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms10100

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().