Dataset Information

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

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 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.

SUBMITTER: Lujan E

PROVIDER: S-EPMC3289376 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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

Lujan Ernesto E Chanda Soham S Ahlenius Henrik H Südhof Thomas C TC Wernig Marius M

Proceedings of the National Academy of Sciences of the United States of America 20120130 7

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 infect ...[more]

PMID: 22308465

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Project description:Mouse fibroblasts could be directly converted into induced neural stem cells (iNSCs), by introducing a set of known transcription factors (TFs). This process, known as direct reprogramming, is an alternative source of NSCs production for cell therapy applications, hence, more common sources for such cells including embryonic stem cell (ESCs) and induced pluripotent stem cell (iPSCs) are also in use. Despite their importance, the exact role of different TFs involved in the conversion of fibroblasts into iNSCs and the interactions between these factors has not been studied.Here, we have used available microarray data to construct a gene regulatory network to understand the dynamic of regulatory interactions during this conversion. We have implemented other types of data such as information regarding TFs binding sites and valid protein-protein interactions to improve the network reliability. The network contained 1857 differentially expressed (DE) genes, linked by11054 interactions. The most important TFs identified based on topology analysis of the network. Furthermore, in selecting such TFs, we have also considered their role in the regulation of nervous system development.Based on these analyses, we found that Ezh2, Jarid2, Mtf2, Nanog, Pou5f1, Sall4, Smarca4, Sox2, Suz12, and Tcf3 are the main regulators of direct conversion of mouse fibroblasts into iNSCs. Because, members of the polycomb repressive complex 2 (PRC2) were present in the most effective TFs' list, we have concluded that this complex is one of the major factors in this conversion. Additionally, gene expression profiling of iNSCs, obtained from a different data sets, showed that Sox2 and Ezh2 are two main regulators of the direct reprogramming process.Our results provide an insight into molecular events that occur during direct reprogramming of fibroblasts into iNSCs. This information could be useful in simplifying the production of iNSCs, by reducing the number of required factors, for use in regenerative medicine.

Dataset Information

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

Publications

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

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