Sox2 roles in neural stem cells

Pevny, Larysa; Nicolis, Silvia K.

doi:10.1016/j.biocel.2009.08.018

Cited by 300 publications

(249 citation statements)

References 34 publications

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“…Sox2 is highly expressed in adult NSCs, is one of the earliest functional markers of neuroectodermal specification in the embryo, and plays a key role in the neural lineage specification (18)(19)(20). We show that Sox2-transduced CB cells acquire a distinct neuronal morphology and express multiple neuronal markers in vitro, and that they can be expanded for as many as 25 passages when cultured in permissive condition culture.…”

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confidence: 79%

Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc

Giorgetti

Marchetto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The finding that certain somatic cells can be directly converted into cells of other lineages by the delivery of specific sets of transcription factors paves the way to novel therapeutic applications. Here we show that human cord blood (CB) CD133 + cells lose their hematopoietic signature and are converted into CB-induced neuronal-like cells (CB-iNCs) by the ectopic expression of the transcription factor Sox2, a process that is further augmented by the combination of Sox2 and c-Myc. Gene-expression analysis, immunophenotyping, and electrophysiological analysis show that CBiNCs acquire a distinct neuronal phenotype characterized by the expression of multiple neuronal markers. CB-iNCs show the ability to fire action potentials after in vitro maturation as well as after in vivo transplantation into the mouse hippocampus. This system highlights the potential of CB cells and offers an alternative means to the study of cellular plasticity, possibly in the context of drug screening research and of future cell-replacement therapies.neurons | reprogramming | stem cells T he fate of adult somatic cells is not fixed rigidly and can be reprogrammed by experimental manipulation. The generation of induced pluripotent stem cells (iPSCs) represents the most dramatic evidence that the epigenome of somatic cells are remarkably plastic (1). Recently, it has been reported that fibroblasts can be converted by ectopic expression of defined transcription factors into postmitotic neurons (2-9), neural progenitors (10, 11), and self-renewing neural stem cells (NSCs) (12, 13). However, most reported methods rely on the use of multiple transcription factors and the use of fibroblasts as donor cells.Here we investigate if cord blood (CB) stem cells can be induced to acquire a neuronal phenotype by using only one transcription factor. It has been previously shown that stem cell populations are more amenable to reprogramming than other somatic cells, probably as a result of their preexisting epigenetic state (14,15). Moreover, because of their biological characteristics and availability, CB cells as a donor cell type could offer clear logistic advantages vs. other adult somatic cell types (16,17). These cells can be collected without any risk for the donor and are young cells carrying minimal somatic mutations.Strikingly, we show that forced expression of Sox2 is sufficient to convert CB CD133 + cells into induced neuronal progenitor (NP)-like cells, a conversion process that is augmented by the coexpression of c-Myc. Sox2 is highly expressed in adult NSCs, is one of the earliest functional markers of neuroectodermal specification in the embryo, and plays a key role in the neural lineage specification (18)(19)(20). We show that Sox2-transduced CB cells acquire a distinct neuronal morphology and express multiple neuronal markers in vitro, and that they can be expanded for as many as 25 passages when cultured in permissive condition culture. Moreover, we show that CB-induced neuronal-like cells (CB-iNCs) are able to differentiate in vitro and ...

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mentioning

confidence: 79%

Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc

Giorgetti

Marchetto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Although SOX2 is arguably a cornerstone of neural stem cell biology (54,55) and plays an essential role in neurogenesis in the developing and adult brain (13), the mechanisms by which SOX2 regulates neuronal differentiation have remained unclear. In our previous study focusing on the LIN28 gene, which is fully active in NPCs, we found that SOX2 promotes an open chromatin state at the promoter (H3K9ac mark) through recruitment of the TRRAP/GCN5 complex (56).…”

Section: Discussionmentioning

confidence: 99%

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

Amador-Arjona

Cimadamore

Huang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

136

120

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Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.SOX2 | neurogenesis | epigenetics C ell fate and differentiation decisions of adult neural progenitor cells (NPCs) are controlled by intrinsic and extrinsic signals from the neurogenic niche (1-3). Recent genomewide analyses of epigenetic regulators in the brain have provided considerable insight into the mechanisms that regulate neural development, neurological disease, and aging (4, 5). The chromatin states of NPCs change dynamically during cell-fate determination and cell differentiation, and chromatin marks such as histone H3 trimethylated Lys 27 (H3K27me3), histone H3 trimethylated Lys 4 (H3K4me3), and histone H3 acetylated Lys 9 (H3K9ac) are essential for regulating the expression of key genes involved in these processes (6). Sex-determining region Y (SRY)-related HMG box 2 (SOX2) is a member of the SOXB1 family of transcription factors, which play important roles in maintaining neural stem/progenitor cell properties, including their capacity to proliferate and self-renew (7,8). In humans, SOX2 mutations are associated with anophthalmia, defective hippocampal development, and seizures (9-11). Most patients with this syndrome experience intellectual disabilities (11), suggesting that loss of SOX2 function affects areas of the brain involved in cognition (e.g., hippocampus). SOX2 deficiency also causes neurodegeneration and impaired neurogenesis in the adult mouse brain (12, 13). However, the molecular mechanisms underlying the function of SOX2 in adult neurogenesis and its role in the human SOX2 anophthalmia syndrome are largely unknown.The subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus is a germinal zone of active neurogenesis during adulthood (14). Indeed, approximately one-third of DG neurons lost during this period are replaced ...

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“…OCT4 and SOX2 are essential for iPS cell differentiation [30]. SOX2 plays a critical role in the maintenance of embryonic and neural stem cells and neural differentiation of MSCs in vitro [25]. Overexpression of OCT4 is essential for generating functional neurons from adult neural stem cells [7].…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Neurosphere Differentiation Potential of Canine Bone Marrow-Derived Mesenchymal Stem Cells and Adipose-Derived Mesenchymal Stem Cells

Chung

Fujita

Kawahara

et al. 2013

The Journal of Veterinary Medical Science

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ABSTRACT. Stem cell transplantation is one of the most promising yet enigmatic treatments for spinal cord injury (SCI), a common problem in dogs. As pre-differentiated mesenchymal stem cells (MSCs) can be expanded and differentiated into neurospheres in vitro, before being transplanted back, they may prove to be more beneficial for treating SCI. Therefore, we compared the endogenous differentiation potential, including the neuronal cell differentiation, of neurospheres from canine bone marrow MSCs (cBMMSCs) with that of the adipose tissuederived MSCs (cADMSCs). Nestin-positive neurospheres were generated from MSCs derived from the bone marrow and adipose tissue. Neuronal cells were differentiated from the neurospheres derived from both these tissues. Gene expression analysis revealed that Nestin, βIII-tubulin, NCAM, OCT4 and SOX2 were expressed in MSCs and the corresponding neurospheres. Notably, cBMMSC-derived neuronal cells expressed higher levels of βIII-tubulin. The mRNA expressions of NANOG, Nestin, OCT4 and SOX2 were upregulated in neurospheres derived from both. Immunofluorescence analysis detected the expression of neuronal markers, namely, βIII-tubulin, GFAP, S100, NF200 and MAP2, in differentiated neuron-like cells. Our findings highlight that both cBMMSCs and cADMSCs could be differentiated into neurospheres and neuron-like cells, and therefore, these cells are suitable candidates for cell transplantation. Further, cADMSCs form a more suitable cell source, as larger number of cells could be harvested from cADMSC-derived neurospheres. Future studies employing in vivo transplantation models to investigate the effectiveness of MSCs for treating SCI are warranted. KEY WORDS: adipose-derived mesenchymal stem cell, bone marrow-derived mesenchymal stem cell, canine, neurosphere, spinal cord injury.

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Sox2 roles in neural stem cells

Cited by 300 publications

References 34 publications

Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc

Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc

SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

A Comparison of Neurosphere Differentiation Potential of Canine Bone Marrow-Derived Mesenchymal Stem Cells and Adipose-Derived Mesenchymal Stem Cells

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