Direct conversion of fibroblasts to functional neurons by defined factors.
Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.
Vierbuchen
Thomas
T
Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, California 94304, USA.
Ostermeier
Austin
A
Pang
Zhiping P
ZP
Kokubu
Yuko
Y
Südhof
Thomas C
TC
Wernig
Marius
M
D000200:Action Potentials; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D019070:Cell Lineage; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D000076104:Oligodendrocyte Transcription Factor 2; D050809:POU Domain Factors / Q000235:genetics / Q000378:metabolism; D044968:Regenerative Medicine; D013569:Synapses / Q000378:metabolism; D013623:Tail / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D050809:POU Domain Factors; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C512773:Olig2 protein, mouse; C492122:Zic1 protein, mouse; C074066:Pou3f2 protein, mouse