Direct Conversion of Human Fibroblasts to Dopaminergic Neurons

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2011 Jun 8

PMID 21646515

Citations 388

Authors

Ulrich Pfisterer

Agnete Kirkeby

Olof Torper

James Wood

Jenny Nelander

Audrey Dufour

Anders Bjorklund

Olle Lindvall

Johan Jakobsson

Malin Parmar

Affiliations

Soon will be listed here.

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 phenotypes when 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 subtype-specific induced neurons derived from human somatic cells could be valuable for disease modeling and cell replacement therapy.

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References

Ferri A, Lin W, Mavromatakis Y, Wang J, Sasaki H, Whitsett J . Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development. 2007; 134(15):2761-9. DOI: 10.1242/dev.000141. View

Breul S, Bradley K, HANCE A, Schafer M, Berg R, Crystal R . Control of collagen production by human diploid lung fibroblasts. J Biol Chem. 1980; 255(11):5250-60. View

Simon H, SAUERESSIG H, Wurst W, Goulding M, OLeary D . Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci. 2001; 21(9):3126-34. PMC: 6762576. View

Miura K, Okada Y, Aoi T, Okada A, Takahashi K, Okita K . Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol. 2009; 27(8):743-5. DOI: 10.1038/nbt.1554. View

Georgievska B, Jakobsson J, Persson E, Ericson C, Kirik D, Lundberg C . Regulated delivery of glial cell line-derived neurotrophic factor into rat striatum, using a tetracycline-dependent lentiviral vector. Hum Gene Ther. 2004; 15(10):934-44. DOI: 10.1089/hum.2004.15.934. View

Zetterstrom R, Solomin L, Jansson L, Hoffer B, Olson L, Perlmann T . Dopamine neuron agenesis in Nurr1-deficient mice. Science. 1997; 276(5310):248-50. DOI: 10.1126/science.276.5310.248. View

Hovatta O, Mikkola M, Gertow K, Stromberg A, Inzunza J, Hreinsson J . A culture system using human foreskin fibroblasts as feeder cells allows production of human embryonic stem cells. Hum Reprod. 2003; 18(7):1404-9. DOI: 10.1093/humrep/deg290. View

Forsberg M, Carlen M, Meletis K, Yeung M, Barnabe-Heider F, Persson M . Efficient reprogramming of adult neural stem cells to monocytes by ectopic expression of a single gene. Proc Natl Acad Sci U S A. 2010; 107(33):14657-61. PMC: 2930460. DOI: 10.1073/pnas.1009412107. View

Zervas M, Millet S, Ahn S, Joyner A . Cell behaviors and genetic lineages of the mesencephalon and rhombomere 1. Neuron. 2004; 43(3):345-57. DOI: 10.1016/j.neuron.2004.07.010. View

10.

Grace A, Onn S . Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. J Neurosci. 1989; 9(10):3463-81. PMC: 6569889. View

11.

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K . Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131(5):861-72. DOI: 10.1016/j.cell.2007.11.019. View

12.

Zufferey R, Nagy D, Mandel R, Naldini L, Trono D . Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol. 1997; 15(9):871-5. DOI: 10.1038/nbt0997-871. View

13.

Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton D . In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008; 455(7213):627-32. PMC: 9011918. DOI: 10.1038/nature07314. View

14.

Vierbuchen T, Ostermeier A, Pang Z, Kokubu Y, Sudhof T, Wernig M . Direct conversion of fibroblasts to functional neurons by defined factors. Nature. 2010; 463(7284):1035-41. PMC: 2829121. DOI: 10.1038/nature08797. View

15.

Acampora D, Mazan S, Lallemand Y, Avantaggiato V, Maury M, Simeone A . Forebrain and midbrain regions are deleted in Otx2-/- mutants due to a defective anterior neuroectoderm specification during gastrulation. Development. 1995; 121(10):3279-90. DOI: 10.1242/dev.121.10.3279. View

16.

Ebert A, Yu J, Rose Jr F, Mattis V, Lorson C, Thomson J . Induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. 2008; 457(7227):277-80. PMC: 2659408. DOI: 10.1038/nature07677. View

17.

Park I, Zhao R, West J, Yabuuchi A, Huo H, Ince T . Reprogramming of human somatic cells to pluripotency with defined factors. Nature. 2007; 451(7175):141-6. DOI: 10.1038/nature06534. View

18.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

19.

Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B . Identification of intrinsic determinants of midbrain dopamine neurons. Cell. 2006; 124(2):393-405. DOI: 10.1016/j.cell.2005.10.037. View

20.

Ieda M, Fu J, Delgado-Olguin P, Vedantham V, Hayashi Y, Bruneau B . Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010; 142(3):375-86. PMC: 2919844. DOI: 10.1016/j.cell.2010.07.002. View