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Neuron. 2014 Oct 22;84(2):311-23. doi: 10.1016/j.neuron.2014.10.016. Epub 2014 Oct 22.

Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts.

Author information

1
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Program in Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, USA.
2
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
3
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, MO 63110, USA.
4
Program in Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO 63110, USA.
5
Departments of Biomedical Engineering and Cell Biology and Physiology, CIMED, Washington University, Saint Louis, MO 63110, USA.
6
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: yooa@wustl.edu.

Abstract

The promise of using reprogrammed human neurons for disease modeling and regenerative medicine relies on the ability to induce patient-derived neurons with high efficiency and subtype specificity. We have previously shown that ectopic expression of brain-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), promoted direct conversion of human fibroblasts into neurons. Here we show that coexpression of miR-9/9*-124 with transcription factors enriched in the developing striatum, BCL11B (also known as CTIP2), DLX1, DLX2, and MYT1L, can guide the conversion of human postnatal and adult fibroblasts into an enriched population of neurons analogous to striatal medium spiny neurons (MSNs). When transplanted in the mouse brain, the reprogrammed human cells persisted in situ for over 6 months, exhibited membrane properties equivalent to native MSNs, and extended projections to the anatomical targets of MSNs. These findings highlight the potential of exploiting the synergism between miR-9/9*-124 and transcription factors to generate specific neuronal subtypes.

PMID:
25374357
PMCID:
PMC4223654
DOI:
10.1016/j.neuron.2014.10.016
[Indexed for MEDLINE]
Free PMC Article

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