Transcriptional profiling of the developmentally important signalling pathways in human embryonic stem cells

Rho, Jeung-Yon; Yu, Kweon; Han, Jee-Soo; Chae, Jung‐Il; Koo, Deog‐Bon; Yoon, Hyunsoo; Moon, Shin-Yong; Lee, Kyung-Kwang; Han, Yong‐Mahn

doi:10.1093/humrep/dei328

Cited by 63 publications

(36 citation statements)

References 58 publications

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“…Human stem and progenitor cell control by the TGF-b superfamily has been extensively studied in vitro with various cell types such as hHSCs, [25][26][27][28] keratinocytes, 29 and more recently, human adult embryonic stem cells (hESCs). [47][48][49][50][51][52][53] Our preliminary study of the effect of TGF-b on MSCs (data not shown) also indicates that blocking TGF-b can activate a subpopulation of highly proliferative progenitor cells. Interestingly, however, the simultaneous addition of neutralizing antibodies for TGF-b and IFN had no additive effect, suggesting that both treatments activated similar cell subpopulations.…”

Section: G12mentioning

confidence: 77%

A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon α/β

et al. 2007

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Type I interferon (IFN) is shown to control the reversible quiescence of a primitive human bone marrow mesenchymal stem cell (MSC) subpopulation. A 24 h pre-treatment of Stro1 þ / GlycoA-or CD45-/GlycoA-subpopulations with a monoclonal antibody (mAb) against the IFNAR1 chain of the human type I IFN receptor (64G12), or with a polyclonal anti-IFNa antibody, resulted in a marked increase in the number of very large colonies (CFU-F 43000 cells) obtained in the presence of low, but necessary, concentrations of bFGF. Over a 2-month culture period, this short activation promoted a faster and greater amplification of mesenchymal progenitors for adipocytes and osteoblasts. Activation correlated with inhibition of STAT1 and STAT2 phosphorylation and of STAT1 nuclear translocation. A non-neutralizing anti-IFNAR1 mAb was ineffective. We demonstrate that control and activated MSCs express ST3GAL3, a sialyltransferase necessary to produce the embryonic antigens SSEA-3 and -4. Interestingly, activated MSC progeny expressed SSEA-3 and -4 at a higher level than control cultures, but this was not correlated with a significant expression of other embryonic markers. As MSCs represent an essential tool in tissue regeneration, the use of 64G12, which rapidly recruits a higher number of primitive cells, might increase amplification safety for cell therapy.

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Section: G12mentioning

confidence: 77%

A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon α/β

et al. 2007

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“…Finally, another pathway that our analysis predicted involves the interaction of the p38 kinase with the MAX TF (MYC associated factor X) known to form complexes along with other proteins for gene regulation (116). In particular, the JAK-STAT pathway is essential for embryonic stem cell renewal and proliferation (117), suggesting that it is still active in the present system.…”

Section: Jak-stat/mapk Signaling Pathwaysmentioning

confidence: 85%

Pathway simulations in common oncogenic drivers of leukemic and rhabdomyosarcoma cells: A systems biology approach

et al. 2012

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Abstract. A part of current research has intensively been focused on the proliferation and metabolic processes governing biological systems. Since the advent of high throughput methodologies such as microarrays, the load of genomic data has increased geometrically and along with that the need for computational methods to interpret these data. In the present study, we investigated in vitro the common proliferation and metabolic processes, associated with common oncogenic pathways, as far as gene expression is concerned, between the T-cell acute lymphoblastic leukemia (CCRF-CEM) and the rhabdomyosarcoma (TE-671) cell lines. We present a computational approach, using cDNA microarrays, in order to identify commonalities between diverse biological systems. Our analysis predicted that JAK1, STAT1, PIAS2 and CDK4 are the driving forces in the two cell lines. This type of analysis may lead to the understanding of the common mechanisms that transform physiological cells to malignant, and may reveal a new holistic approach to understanding the dynamics of tumor onset as well as the mechanistics behind oncogenic drivers. IntroductionIt is a fact that tumors can be as diverse as the patients carrying them. Due to these differences, tumors are extremely difficult to cure, as the effects of treatments differ depending on the patient. Previously, Nicolis showed that stem cells are found in different tumor types, suggesting that they can be the etiology of tumor maintenance and growth (1). However, there is evidence that even normal, already differentiated cells can be transformed into tumorigenic ones (1). Perilongo et al also reported a case of a child manifesting five different tumor types simultaneously (2). It may be possible that stem cells originating from the same organism possess similar mutations or alterations, thus giving rise to five different tumor types. Therefore, there is a need for the investigation of common pathways between different tumor types. The discovery of similar or opposite gene expression profiles could lead us to the understanding of a common tumor origin, if such exists.A number of studies have investigated the detection of cancer germ line genes (CGGs) both in pediatric sarcomas (3) and pediatric brain tumors (4). The discovery of global antigens for tumor vaccines could become salvatory for childhood malignancies (3). Other studies have reported the common appearance of antigens in Ewing's sarcoma/primitive neuroectodermal tumor (EWS/PNET) with lymphoblastic lymphoma (5). Rhabdomyosarcoma (RMS) belongs to the PNET family of tumors, which utilize embryonic genes for their progression (6). Acute lymphoblastic leukemia (ALL), which originates from the lymphoblast, also uses embryonic mechanisms for its differentiation and progression.Another point which requires attention is the regulation of genes through transcription factors (TFs). Knowledge of gene regulatory networks is considered to be of crucial importance for understanding diseases such as cancer, and may lead to new therapeutic approaches...

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“…TGF-␤/Nodal/activin, FGF, Wnt, and BMP are all potent mesoderm inducers in vertebrates, 2 and previous reports have demonstrated that hES cells also express components of these 4 signaling transduction pathways [25][26][27] ( Figure 1A); however, whether these mesoderm inducers function in hES cells remains unclear. Here, we tested the effects of exogenous activin A, bFGF, Wnt3a, and BMP-4 on the mesoderm initiation in hES cells, as determined by the expression analysis of the pan-mesoderm marker brachyury.…”

Section: Differential Effects Of Short-term and Long-term Bmp-4 Treatmentioning

confidence: 90%

Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells

Zhang

Tan

et al. 2008

Blood

276

219

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IntroductionThe vertebrate mesoderm gives rise to a diverse variety of tissues, including the heart, vasculature, and blood. It is formed in the primitive streak (PS) which appears first in the posterior epiblast during gastrulation. The nascent PS then elongates to the anterior part, whereas the epiblast cells ingress through the PS, migrate to appropriate location in the embryo, and become either mesoderm or definitive endoderm. 1 Although the process of mesoderm formation is well understood, the underlying molecular mechanisms remain poorly defined.Previous studies have identified several signaling pathways involved in this process. 2 One is the transforming growth factorbeta (TGF-␤) superfamily member, bone morphogenetic protein-4 (BMP-4). Like other TGF-␤ superfamily members, BMP-4 binds to and brings together the type I and type II receptors on the cell surface, which allows receptor II to phosphorylate the receptor I kinase domain. After this activation, the type I receptor phosphorylates certain members of the Smad proteins (Smad 1, 5, 8; R-Smad). Two phosphorylated R-Smads, in combination with a common mediator Smad (Smad4; Co-Smad), form a heterotrimeric complex, which then translocates into the nucleus and cooperates with other transcription factors to modulate target gene expression. [3][4][5][6] Genetic studies in mice have shown that BMP-4 signaling is required for mesoderm formation. [7][8][9] Mice deficient in the BMP-4 ligand, 7 in the BMP type II receptor, 8 or in a BMP type I receptor Alk3, 9 all fail to develop mesoderm. It has also been demonstrated that BMP-4 plays critical roles in mesoderm induction and mesoderm lineage differentiation from mouse embryonic stem cells (mES cells). [10][11][12][13][14][15][16][17][18][19] The key role of BMP-4 in mouse embryos and mES cells has led us to investigate its function in human embryonic stem cells (hES cells), the differentiation of which can, at least in part, mimic the human embryogenesis. 20,21 Xu et al 22 showed that long-term BMP-4 treatment (up to 7 days) induces hES cell differentiation into trophoblast. Later, Pera et al 23 demonstrated that activation of the same signaling pathway by BMP-2 in hES cells results in the formation of extra-embryonic endoderm. Surprisingly, we found that short-term BMP-4 treatment (24 hours) initiated mesoderm induction at a high efficiency in hES cells. In addition, these mesoderm progenitor cells were able to differentiate into various mesoderm lineages. The differential effects of short-term and long-term BMP-4 treatments on hES cell differentiation suggest that the BMP signaling pathway might play a flexible and time-dependent role in human embryonic development and cell fate determination. Methods Cell culture and differentiationThe H1, H7, and H9 hES cell lines were obtained from WiCell Research Institute (Madison, WI). Cells were cultured and passaged on mitomycin C-treated mouse embryonic fibroblast (MEF) feeders in hES cell culture Submitted February 14, 2007; accepted November 20, 2007. Prepublished...

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Transcriptional profiling of the developmentally important signalling pathways in human embryonic stem cells

Abstract: The self-renewal of hESC is probably maintained by coordinated regulation of signalling-specific molecules and in a signalling-specific manner.

Cited by 63 publications

References 58 publications

A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon α/β

A sub-population of high proliferative potential-quiescent human mesenchymal stem cells is under the reversible control of interferon α/β

Pathway simulations in common oncogenic drivers of leukemic and rhabdomyosarcoma cells: A systems biology approach

Short-term BMP-4 treatment initiates mesoderm induction in human embryonic stem cells

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