Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons

Meng-Lu Liu, Tong Zang, Yuhua Zou, Joshua C. Chang, Jay R. Gibson, Kimberly M. Huber and Chun-Li Zhang ()
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Meng-Lu Liu: University of Texas Southwestern Medical Center
Tong Zang: University of Texas Southwestern Medical Center
Yuhua Zou: University of Texas Southwestern Medical Center
Joshua C. Chang: University of Texas Southwestern Medical Center
Jay R. Gibson: University of Texas Southwestern Medical Center
Kimberly M. Huber: University of Texas Southwestern Medical Center
Chun-Li Zhang: University of Texas Southwestern Medical Center

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: Abstract Cell fate can be reprogrammed by modifying intrinsic and extrinsic cues. Here we show that two small molecules (forskolin and dorsomorphin) enable the transcription factor Neurogenin 2 (NGN2) to convert human fetal lung fibroblasts into cholinergic neurons with high purity (>90%) and efficiency (up to 99% of NGN2-expressing cells). The conversion is direct without passing through a proliferative progenitor state. These human induced cholinergic neurons (hiCN) show mature electrophysiological properties and exhibit motor neuron-like features, including morphology, gene expression and the formation of functional neuromuscular junctions. Inclusion of an additional transcription factor, SOX11, also efficiently converts postnatal and adult skin fibroblasts from healthy and diseased human patients to cholinergic neurons. Taken together, this study identifies a simple and highly efficient strategy for reprogramming human fibroblasts to subtype-specific neurons. These findings offer a unique venue for investigating the molecular mechanisms underlying cellular plasticity and human neurodegenerative diseases.

Date: 2013
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DOI: 10.1038/ncomms3183

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