Proneural Transcription Factor Atoh1 Drives Highly Efficient Differentiation of Human Pluripotent Stem Cells Into Dopaminergic Neurons. (5th June 2014)

• Record Type: Journal Article
• Authors: Sagal, Jonathan; Zhan, Xiping; Xu, Jinchong; Tilghman, Jessica; Karuppagounder, Senthilkumar S.; Chen, Li; Dawson, Valina L.; Dawson, Ted M.; Laterra, John; Ying, Mingyao
• Is Part Of: Stem cells translational medicine. Volume 3:Number 8(2014)
• Page Start: 888
• Page End: 898
• Publication Date: 2014-06-05
• Subjects: Induced pluripotent stem cells -- Embryonic stem cells -- Parkinson's disease -- Basic helix-loop-helix transcription factors -- Tet-On; Stem cells -- Periodicals; Regenerative medicine -- Periodicals; Periodicals; 616.0277405
• DOI: 10.5966/sctm.2013-0213
• Languages: English
• ISSNs: 2157-6564

Abstract

Abstract : To fully use human pluripotent stem cells (PSCs) in regenerative medicine, highly efficient differentiation strategies are required to drive induced PSCs into desired lineages and generate functional cell progenies. Current differentiation protocols for deriving dopaminergic neurons from PSCs involve months of stem cell culture procedures and multiple reagents. This study was motivated by a desire for a rapid and highly efficient system to generate human PSC-derived functional dopaminergic neurons. Abstract: Human pluripotent stem cells (PSCs) are a promising cell resource for various applications in regenerative medicine. Highly efficient approaches that differentiate human PSCs into functional lineage-specific neurons are critical for modeling neurological disorders and testing potential therapies. Proneural transcription factors are crucial drivers of neuron development and hold promise for driving highly efficient neuronal conversion in PSCs. Here, we study the functions of proneural transcription factor Atoh1 in the neuronal differentiation of PSCs. We show that Atoh1 is induced during the neuronal conversion of PSCs and that ectopic Atoh1 expression is sufficient to drive PSCs into neurons with high efficiency. Atoh1 induction, in combination with cell extrinsic factors, differentiates PSCs into functional dopaminergic (DA) neurons with >80% purity. Atoh1-induced DA neurons recapitulate key biochemical and electrophysiological features of midbrain DA neurons, the degeneration of which is responsible for clinical symptoms in Parkinson's disease (PD). Atoh1-induced DA neurons provide a reliable disease model for studying PD pathogenesis, such as neurotoxin-induced neurodegeneration in PD. Overall, our results determine the role of Atoh1 in regulating neuronal differentiation and neuron subtype specification of human PSCs. Our Atoh1-mediated differentiation approach will enable large-scale applications of PD patient-derived midbrain DA neurons in mechanistic studies and drug screening for both familial and sporadic PD.