TY - JOUR
T1 - Generation of Human Striatal Neurons by MicroRNA-Dependent Direct Conversion of Fibroblasts
AU - Victor, Matheus B.
AU - Richner, Michelle
AU - Hermanstyne, Tracey O.
AU - Ransdell, Joseph L.
AU - Sobieski, Courtney
AU - Deng, Pan Yue
AU - Klyachko, Vitaly A.
AU - Nerbonne, Jeanne M.
AU - Yoo, Andrew S.
N1 - Funding Information:
We thank S. Dahiya and C. Huh for providing human striatum sections and performing laser microdissections and A. Soleiman for technical assistance. We thank J.D. Surmeier, S. Zakharenko, S. Mennerick, L. Solica-Krezel, and D. Abernathy for helpful suggestions with the manuscript; the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with single-cell analysis; J. Ho and J. Richner for help with FACS sorting; and J. Dougherty for TRAP data analysis. M.B.V. is supported by the National Science Foundation Graduate Research Fellowship (DGE-1143954). C.S. is supported by the fellowship from Cognitive, Computational and Systems Neuroscience Pathway (T32N5023547) and a grant from NIH, MH078823. J.M.N. is supported by the National Institute of General Medical Sciences (R01 GM104991) and the National Heart Lung and Blood Institute (T.O.H. is supported by T32 HL007275). A.S.Y. is supported by NIH Director’s Innovator Award (DP2) and awards from the Mallinckrodt Jr. Foundation, Ellison Medical Foundation, and Presidential Early Career Award for Scientists and Engineers.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/10/22
Y1 - 2014/10/22
N2 - 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 insitu for over 6months, 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.
AB - 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 insitu for over 6months, 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.
UR - http://www.scopus.com/inward/record.url?scp=84908231578&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2014.10.016
DO - 10.1016/j.neuron.2014.10.016
M3 - Article
C2 - 25374357
AN - SCOPUS:84908231578
SN - 0896-6273
VL - 84
SP - 311
EP - 323
JO - Neuron
JF - Neuron
IS - 2
ER -