Direct conversion of human fibroblasts to dopaminergic neurons

Ulrich Pfisterer; Agnete Kirkeby; Olof Torper; James Wood; Jenny Nelander; Audrey Dufour; Anders Björklund; Olle Lindvall; Johan Jakobsson; Malin Parmar

doi:10.1073/pnas.1105135108

Direct conversion of human fibroblasts to dopaminergic neurons

Ulrich Pfisterer, Agnete Kirkeby, Olof Torper, James Wood, Jenny Nelander, Audrey Dufour, Anders Björklund, Olle Lindvall, Johan Jakobsson, Malin Parmar^*

^*Corresponding author for this work

Laboratory

533 Citations (Scopus)

Abstract

Recent reports demonstrate that somatic mouse cells can be directly converted to other mature cell types by using combined expression of defined factors. Here we show that the same strategy can be applied to human embryonic and postnatal fibroblasts. By overexpression of the transcription factors Ascl1, Brn2, and Myt1l, human fibroblasts were efficiently converted to functional neurons. We also demonstrate that the converted neurons can be directed toward distinct functional neurotransmitter phenotypeswhen the appropriate transcriptional cues are provided together with the three conversion factors. By combining expression of the three conversion factors with expression of two genes involved in dopamine neuron generation, Lmx1a and FoxA2, we could direct the phenotype of the converted cells toward dopaminergic neurons. Such subtypespecific induced neurons derived from human somatic cells could be valuable for disease modeling and cell replacement therapy.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	108
Issue number	25
Pages (from-to)	10343-10348
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1105135108
Publication status	Published - 21 Jun 2011

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AU - Pfisterer, Ulrich

AU - Kirkeby, Agnete

AU - Torper, Olof

AU - Wood, James

AU - Nelander, Jenny

AU - Dufour, Audrey

AU - Björklund, Anders

AU - Lindvall, Olle

AU - Jakobsson, Johan

AU - Parmar, Malin

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AB - Recent reports demonstrate that somatic mouse cells can be directly converted to other mature cell types by using combined expression of defined factors. Here we show that the same strategy can be applied to human embryonic and postnatal fibroblasts. By overexpression of the transcription factors Ascl1, Brn2, and Myt1l, human fibroblasts were efficiently converted to functional neurons. We also demonstrate that the converted neurons can be directed toward distinct functional neurotransmitter phenotypeswhen the appropriate transcriptional cues are provided together with the three conversion factors. By combining expression of the three conversion factors with expression of two genes involved in dopamine neuron generation, Lmx1a and FoxA2, we could direct the phenotype of the converted cells toward dopaminergic neurons. Such subtypespecific induced neurons derived from human somatic cells could be valuable for disease modeling and cell replacement therapy.

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Direct conversion of human fibroblasts to dopaminergic neurons

Abstract

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