Direct conversion of fibroblasts to functional neurons by defined factors

By Thomas Vierbuchen, Austin Ostermeier, Z. Pang, Yuko Kokubu, T. Sūdhof, Marius Wernig. Nature, 2010

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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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6238813703b3729ca42d84a9caad62fe2de67983

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Citations in the corpus

Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration (2011, background): “Using a similar strategy, it is also possible to transdifferentiate mouse fibroblasts into functional neurons using just three transcription factors: achaete–scute homologue 1 (ASCL1), brain-specific homeobox and POU domain 2 (BRN2; also known as POU3F2) and myelin transcription factor 1-like (MYT1L”
Nuclear reprogramming to a pluripotent state by three approaches (2010, background): “and colleagues determined for generating iPS cells, two research groups (led by Melton and by Wernig) have deciphered the individual contributions of a panoply of transcription factors, identifying three that can convert one cell type to another (factors that can convert, for example, exocrine cells”
Induced pluripotent stem cells: past, present, and future. (2012, background): “It should be noted that variations among ESC clones have been well documented (Osafune et al., 2008; Ward et al., 2004).”
Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease (2012, background): “FBs can also be reprogrammed into different cell types, such as pluripotent stem cells [53], myoblasts [54], neurons [55].”
In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model (2013, background): “Many studies have since demonstrated transdifferentiation across different cell lineages, including reprogramming mouse or human fibroblasts directly into neurons (Ambasudhan et al., 2011; Caiazzo et al., 2011; Kim et al., 2011; Ladewig et al., 2012; Liu et al., 2012, 2013; Meng et al., 2012; Pang e”
Induced pluripotency: history, mechanisms, and applications. (2010, background): “2008); the conversion of fibroblasts into neurons by the activation of the neural factors Ascl1, Brn2, and Myt1l (Vierbuchen et al. 2010); and the conversion of fibroblasts into cardiomyocytes by the cardiac factors Gata4, Mef2c, and Tbx5 (Ieda et al.”
Emerging trends and new developments in regenerative medicine: a scientometric update (2000 – 2014) (2014, background): “1 Warren et al. (2010) CELL STEM CELL, V7, P618 [45] 113.0 2011 2014 2 Kim et al. (2010) NATURE, V467, P285 [32] 102.8 2011 2014 3 Vierbuchen et al. (2010) NATURE, V463, P1035 [23] 93.7 2011 2014 4 Ieda et al. (2010) CELL, V142, P375 [22] 90.7 2011 2014 5 Lister et al. (2011) NATURE, V471, P68 [46]…”
Biopharmaceutical benchmarks 2010 (2010, background): “Particularly noteworthy is the recent finding that fibroblasts can be converted directly into neurons through expression of just three cellular transcription factor”
Direct conversion of human fibroblasts to dopaminergic neurons (2011, methodology): “When investigating the neurotransmitter phenotype of the converted neurons, we found that, similar to what has been reported for mouse iN cells (10), neurons of both excitatory glutamatergic and inhibitory GABAergic phenotypes were present in the cultures (Fig.”