Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts.
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.
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.
Matheus B
MB
Victor
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Michelle
M
Richner
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.
Tracey O
TO
Hermanstyne
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.
Joseph L
JL
Ransdell
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.
Courtney
C
Sobieski
Departments of Biomedical Engineering and Cell Biology and Physiology, CIMED, Washington University, Saint Louis, MO 63110, USA.
Pan-Yue
PY
Deng
Departments of Biomedical Engineering and Cell Biology and Physiology, CIMED, Washington University, Saint Louis, MO 63110, USA.
Vitaly A
VA
Klyachko
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.
Jeanne M
JM
Nerbonne
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: yooa@wustl.edu.
Andrew S
AS
Yoo
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D017072:Neostriatum / Q000166:cytology*; D009474:Neurons / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D035683:MicroRNAs; D014157:Transcription Factors