Oct4-Induced Pluripotency in Adult Neural Stem Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE12499 | GEO | 2009/02/01
SECONDARY ACCESSION(S): PRJNA112981
REPOSITORIES: GEO
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Project description:Induced pluripotent stem (iPS) cells have been generated from mouse and human somatic cells by ectopic expression of the four transcription factors (OCT4, SOX2, c-MYC, KLF4). We previously reported that Oct4 alone is sufficient to directly reprogram adult mouse neural stem cells (NSCs) to iPS cells. Here, we report the generation of one-factor (1F) human iPS from human NSCs (1F hNiPS) by ectopic expression of Oct4 alone. 1F hNiPS cells resemble human embryonic stem cells (hESCs) in global gene expression profiles, epigenetic status and pluripotency in vitro and in vivo. These findings demonstrate that the transcription factor OCT4 is sufficient to reprogram human NSCs to pluripotency. 1F iPS cell generation will accelerate this field further towards understanding reprogramming and generating patient-specific pluripotent stem cells.
2009-09-23 | GSE15355 | GEO
Project description:Pluripotency can be induced in murine and human fibroblast by transduction of four transcription factors (Oct4, Sox2, Klf4 and c-Myc). Previously we reported that two factors (Oct4 and Klf4) are sufficient for reprogramming adult mouse neural stem cells (NSCs) to a pluripotent state. However, although NSCs endogenously express the factors Sox2, c-Myc, and Klf4, our previous report does not elucidate why exogenous expression of either Klf4 or c-Myc is still required for reprogramming. Here we report that exogenous expression of Oct4 is sufficient to generate one-factor induced pluripotent stem (1F iPS) cells without any oncogenic factors, such as c-Myc and Klf4, from mouse adult NSCs, which endogenously express Sox2, c-Myc, and Klf4, and also intermediate reprogramming markers alkaline phosphatase (AP), stage-specific embryonic antigen-1 (SSEA-1). These results extend our previous report proposing that somatic cells can be reprogrammed to a pluripotent state with a reducing number of reprogramming factors when the complementing factors are endogenously expressed in the somatic cells. Experiment Overall Design: 10 hybridizations in total. Experiment Overall Design: NSC-derived iPS cells by one-factor (Oct4) in triplicate: Experiment Overall Design: - NSC_1F_iPS_1 Experiment Overall Design: - NSC_1F_iPS_2 Experiment Overall Design: - NSC_1F_iPS_3 Experiment Overall Design: One-factor (Oct4) iPS cell-derived NSC in triplicate: Experiment Overall Design: - 1F_iPS_NSC_1 Experiment Overall Design: - 1F_iPS_NSC_2 Experiment Overall Design: - 1F_iPS_NSC_3 Experiment Overall Design: Neural stem cell (NSC) derived from brain of OG2/Rosa26 mice: Experiment Overall Design: - NSC_1 Experiment Overall Design: - NSC_2 Experiment Overall Design: - NSC_3 Experiment Overall Design: - NSC_4
2009-02-08 | E-GEOD-12499 | biostudies-arrayexpress
Project description:Induced pluripotent stem (iPS) cells have been generated from mouse and human somatic cells by ectopic expression of the four transcription factors (OCT4, SOX2, c-MYC, KLF4). We previously reported that Oct4 alone is sufficient to directly reprogram adult mouse neural stem cells (NSCs) to iPS cells. Here, we report the generation of one-factor (1F) human iPS from human NSCs (1F hNiPS) by ectopic expression of Oct4 alone. 1F hNiPS cells resemble human embryonic stem cells (hESCs) in global gene expression profiles, epigenetic status and pluripotency in vitro and in vivo. These findings demonstrate that the transcription factor OCT4 is sufficient to reprogram human NSCs to pluripotency. 1F iPS cell generation will accelerate this field further towards understanding reprogramming and generating patient-specific pluripotent stem cells. For transcriptome profiling, 400 ng of total DNA-free RNA was used as input for labelled cRNA synthesis (Illumina TotalPrep RNA Amplification Kit - Ambion) following the manufacturer's instructions (IVT: 10h). Quality-checked cRNA samples were hybridized as biological or technical duplicates for 18 h onto HumanRef-8 v3 expression BeadChips (Illumina), washed, stained, and scanned following guidelines and using materials / instrumentation supplied / suggested by the manufacturer. Five sample types were analyzed, each one of them in duplicate. hNSC: human fetal neural stem cells (duplicates); 1F hNiPS: One factor (Oct4) human iPS cells from hNSCs, hand-picked cols (duplicates); 2F hNiPS: Two factors (Oct4,Klf4) human iPS cells from hNSCs, hand-picked cols (duplicates); H9 hESC: H9 human ESCs grown on low-density CF1 MEFs (duplicates); H1 hESC: H1 human ESCs grown on low-density CF1 MEFs (duplicates).
2010-05-20 | E-GEOD-15355 | biostudies-arrayexpress
Project description:Reprogramming of somatic cells is a valuable tool to understand the mechanisms of regaining pluripotency and further opens up the possibility to generate patient-specific pluripotent stem cells. Reprogramming of mouse and human somatic cells into pluripotent stem cells, designated as induced pluripotent stem (iPS) cells, has been possible with the expression of the transcription factor quartet Oct4, Sox2, c-Myc, and Klf4. Considering that ectopic expression of c-Myc causes tumourigenicity in offspring and retroviruses themselves can cause insertional mutagenesis, the generation of iPS cells with a minimal number of factors may hasten the clinical application of this approach. Here, we show that adult mouse neural stem cells (NSCs) express higher endogenous levels of Sox2 and c-Myc than ES cells and that exogenous Oct4 together with either Klf4 or c-Myc are sufficient to generate iPS cells from NSCs. These two-factor (2F) iPS cells are similar to embryonic stem cells at the molecular level, contribute to development of the germline, and form chimeras. We propose that, in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors. Experiment Overall Design: 8 hybridizations in total. Experiment Overall Design: NSC derived iPS cells by 2 factors (Oct4 and Klf4) in triplicate: Experiment Overall Design: - iPS cell_2F_1 Experiment Overall Design: - iPS cell_2F_2 Experiment Overall Design: - iPS cell_2F_3 Experiment Overall Design: Embryonic Stem cells (ESC) in triplicate: Experiment Overall Design: - ESC_1 Experiment Overall Design: - ESC_2 Experiment Overall Design: - ESC_3 Experiment Overall Design: NSC cultures in duplicates: Experiment Overall Design: - NSC_2 Experiment Overall Design: - NSC_3 Experiment Overall Design: NSC derived iPS cells by 4 factors (Oct4, Sox2, c-Myc and Klf4) in triplicate: Experiment Overall Design: - iPS cell_4F_1 Experiment Overall Design: - iPS cell_4F_2 Experiment Overall Design: - iPS cell_4F_3
2008-10-20 | E-GEOD-10806 | biostudies-arrayexpress
Project description:Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by Oct4, Sox2, Klf4, plus c-Myc. Recently, Sox2 plus Oct4 were shown to reprogram fibroblasts and Oct4 alone to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here we report that Bmi1 leads to dedifferentiation of mouse fibroblasts into NSC-like cells and, in combination with Oct4, replaces Sox2, Klf4 and c-Myc during reprogramming fibroblasts to iPS cells. Furthermore, activation of sonic hedgehog signalling (by Shh, purmorphamine, or oxysterol) replaces the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One-and two-factor iPS cells are similar to mouse embryonic and adult fibroblasts into iPS cells in global gene expression profile, epigenetic status, in vitro and in bibo differentiation into all three ferm layers, as well as teratoma formation and germline transmission in vivo. These data support that fibroblasts can be reprogrammed into iPS cells by Oct4 alone. Total RNAs were isolated from indicated cells and labeled with Cy3. Hybridization was performed once for each sample.
2010-09-18 | E-GEOD-24208 | biostudies-arrayexpress
Project description:Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by Oct4, Sox2, Klf4, plus c-Myc. Recently, Sox2 plus Oct4 were shown to reprogram fibroblasts and Oct4 alone to reprogram mouse and human neural stem cells (NSCs) into iPS cells. Here we report that Bmi1 leads to dedifferentiation of mouse fibroblasts into NSC-like cells and, in combination with Oct4, replaces Sox2, Klf4 and c-Myc during reprogramming fibroblasts to iPS cells. Furthermore, activation of sonic hedgehog signalling (by Shh, purmorphamine, or oxysterol) replaces the effects of Bmi1, and, in combination with Oct4, reprograms mouse embryonic and adult fibroblasts into iPS cells. One-and two-factor iPS cells are similar to mouse embryonic and adult fibroblasts into iPS cells in global gene expression profile, epigenetic status, in vitro and in bibo differentiation into all three ferm layers, as well as teratoma formation and germline transmission in vivo. These data support that fibroblasts can be reprogrammed into iPS cells by Oct4 alone.
2010-09-18 | GSE24208 | GEO
Project description:Brief expression of pluripotency-associated factors such as OCT4, KLF4, SOX2 and c-MYC (OKSM), in combination with differentiation-inducing signals, was reported to trigger transdifferentiation of fibroblasts into alternative cell types. Here, we show that OKSM expression gives rise to both induced pluripotent stem cells (iPSCs) and iNSCs under conditions that were previously shown to induce only NSC transdifferentiation. Fibroblast-derived iNSC colonies silenced retroviral transgenes and reactivated silenced X chromosomes, both hallmarks of pluripotent stem cells. Moreover, lineage tracing via an Oct4-CreER labeling system demonstrated that virtually all iNSC colonies originate from cells transiently expressing Oct4, whereas ablation of Oct4-positive cells prevented iNSC formation. Lastly, use of an alternative transdifferentiation cocktail that lacks OCT4 and was reportedly unable to support induced pluripotency, yielded iPSCs and iNSCs carrying the Oct4-CreER-derived lineage label. Together, these data suggest that iNSC generation using OKSM and related reprogramming factors requires passage through a transient iPSC state. 5 samples were anlyzed in total, 2 induced pluripotent stem cells (iPSCs), 1 neural stem cells (NSCs) and 2 induced NSCs (iNSCs)
2015-04-30 | E-GEOD-65951 | biostudies-arrayexpress
Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells
A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation.
This model is described in the article:
In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.
Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R
BMC Genomics, 2009, 10:314
Abstract:
BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency.
RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation.
CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies.
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2005-01-01 | MODEL1305010000 | BioModels
Project description:For years, reprogramming factors that induce pluripotency have been identified primarily from ESC-enriched factors, pluripotency-associated factors such as Oct4, Sox2, Klf4, c-Myc, Nanog, Esrrb, Sall4, Utf1, Lin28, PRDM14, and Tet2. Through genome-wide screen we identified novel regulators of reprogramming. Our study is the first proof-of-principle report to suggest a putative general mathematical model. This model provides novel mechanistic insight into the fundamental understanding of the establishment of cellular identity during programming and reprogramming. Through genome-wide screen to identify novel factors of reprogramming in addition to Oct4, Sox2, Klf4, cMyc Through genome-wide screen to identify novel factors of reprogramming in addition to Oct4, Sox2, Klf4, cMyc. Induced pluripotent stem cells versus mouse embryonic fibroblast.
2013-05-28 | E-GEOD-47441 | biostudies-arrayexpress
Project description:Differentiated somatic cells can be reprogrammed into induced pluripotent stem cells by ectopic expression of transcription factors Oct4, Sox2, Klf4, and c-Myc, but the mechanisms are still to be dissected. The stoichiometry of factors influences the efficiency of induced pluripotent stem cells, and previous studies emphasized the requirement of high levels of overexpressed Oct4. In this study, we showed that, with appropriate stoichiometry achieved by polycistronic cassettes, Sox2 and Klf4 were sufficient to initiate and establish pluripotency in differentiated cells efficiently without Oct4 overexpression.
2020-01-01 | GSE98280 | GEO