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Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells

Lujan, Ernesto ; Chanda, Soham ; Ahlenius, Henrik LU ; Südhof, Thomas C. and Wernig, Marius (2012) In Proceedings of the National Academy of Sciences of the United States of America 109(7). p.2527-2532
Abstract

We recently showed that defined sets of transcription factors are sufficient to convert mouse and human fibroblasts directly into cells resembling functional neurons, referred to as "induced neuronal"(iN) cells. For some applications however, it would be desirable to convert fibroblasts into proliferative neural precursor cells (NPCs) instead of neurons. We hypothesized that NPC-like cells may be induced using the same principal approach used for generating iN cells. Toward this goal, we infected mouse embryonic fibroblasts derived from Sox2-EGFP mice with a set of 11 transcription factors highly expressed in NPCs. Twenty-four days after transgene induction, Sox2-EGFP + colonies emerged that expressed NPC-specific genes and... (More)

We recently showed that defined sets of transcription factors are sufficient to convert mouse and human fibroblasts directly into cells resembling functional neurons, referred to as "induced neuronal"(iN) cells. For some applications however, it would be desirable to convert fibroblasts into proliferative neural precursor cells (NPCs) instead of neurons. We hypothesized that NPC-like cells may be induced using the same principal approach used for generating iN cells. Toward this goal, we infected mouse embryonic fibroblasts derived from Sox2-EGFP mice with a set of 11 transcription factors highly expressed in NPCs. Twenty-four days after transgene induction, Sox2-EGFP + colonies emerged that expressed NPC-specific genes and differentiated into neuronal and astrocytic cells. Using stepwise elimination, we found that Sox2 and FoxG1 are capable of generating clonal self-renewing, bipotent induced NPCs that gave rise to astrocytes and functional neurons. When we added the Pou and Homeobox domain-containing transcription factor Brn2 to Sox2 and FoxG1, we were able to induce tripotent NPCs that could be differentiated not only into neurons and astrocytes but also into oligodendrocytes. The transcription factors FoxG1 and Brn2 alone also were capable of inducing NPC-like cells; however, these cells generated less mature neurons, although they did produce astrocytes and even oligodendrocytes capable of integration into dysmyelinated Shiverer brain. Our data demonstrate that direct lineage reprogramming using target cell-type-specific transcription factors can be used to induce NPC-like cells that potentially could be used for autologous cell transplantation-based therapies in the brain or spinal cord.

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author
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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Induced neural precursor cells
in
Proceedings of the National Academy of Sciences of the United States of America
volume
109
issue
7
pages
2527 - 2532
publisher
National Academy of Sciences
external identifiers
  • pmid:22308465
  • scopus:84857136772
ISSN
0027-8424
DOI
10.1073/pnas.1121003109
language
English
LU publication?
no
id
a0c7e781-9e48-4698-8bc8-b02ba35569ce
date added to LUP
2025-08-26 11:20:31
date last changed
2025-08-26 11:55:50
@article{a0c7e781-9e48-4698-8bc8-b02ba35569ce,
  abstract     = {{<p>We recently showed that defined sets of transcription factors are sufficient to convert mouse and human fibroblasts directly into cells resembling functional neurons, referred to as "induced neuronal"(iN) cells. For some applications however, it would be desirable to convert fibroblasts into proliferative neural precursor cells (NPCs) instead of neurons. We hypothesized that NPC-like cells may be induced using the same principal approach used for generating iN cells. Toward this goal, we infected mouse embryonic fibroblasts derived from Sox2-EGFP mice with a set of 11 transcription factors highly expressed in NPCs. Twenty-four days after transgene induction, Sox2-EGFP <sup>+</sup> colonies emerged that expressed NPC-specific genes and differentiated into neuronal and astrocytic cells. Using stepwise elimination, we found that Sox2 and FoxG1 are capable of generating clonal self-renewing, bipotent induced NPCs that gave rise to astrocytes and functional neurons. When we added the Pou and Homeobox domain-containing transcription factor Brn2 to Sox2 and FoxG1, we were able to induce tripotent NPCs that could be differentiated not only into neurons and astrocytes but also into oligodendrocytes. The transcription factors FoxG1 and Brn2 alone also were capable of inducing NPC-like cells; however, these cells generated less mature neurons, although they did produce astrocytes and even oligodendrocytes capable of integration into dysmyelinated Shiverer brain. Our data demonstrate that direct lineage reprogramming using target cell-type-specific transcription factors can be used to induce NPC-like cells that potentially could be used for autologous cell transplantation-based therapies in the brain or spinal cord.</p>}},
  author       = {{Lujan, Ernesto and Chanda, Soham and Ahlenius, Henrik and Südhof, Thomas C. and Wernig, Marius}},
  issn         = {{0027-8424}},
  keywords     = {{Induced neural precursor cells}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{7}},
  pages        = {{2527--2532}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells}},
  url          = {{http://dx.doi.org/10.1073/pnas.1121003109}},
  doi          = {{10.1073/pnas.1121003109}},
  volume       = {{109}},
  year         = {{2012}},
}