Genetic basis for developmental toxicity due to statin intake using embryonic stem cell differentiation model

2015 ◽  
Vol 34 (10) ◽  
pp. 965-984 ◽  
Author(s):  
S Jyoti ◽  
S Tandon
Keyword(s):  
Animal Studies ◽  
Developmental Toxicity ◽  
Quantitative Polymerase Chain Reaction ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Key Factor ◽  
Neurofilament 200 ◽  
Differentiation Model

The in utero environment is a key factor controlling the fate of the growing embryo. The deleterious effects of statins during the fetal development are still not very well understood. Data from animal studies and retrospective studies performed in pregnant women give conflicting reports. In this study, using in vitro differentiation model of embryonic stem cells, which mimic the differentiation process of the embryo, we have systematically exposed the cells to lipophilic statins, simvastatin, and atorvastatin at various doses and at critical times during differentiation. The analysis of key genes controlling the differentiation into ecto-, meso- and endodermal lineages was assessed by quantitative polymerase chain reaction. Our results show that genes of the mesodermal lineage were most sensitive to statins, leading to changes in the transcript levels of brachyury, Flk-1, Nkx2.5, and α/β-myosin heavy chain. In addition, changes to endodermal marker α-fetoprotein, along with ectodermal Nes and Neurofilament 200 kDa, imply that during early differentiation exposure to these drugs leads to altered signaling, which could translate to the congenital abnormalities seen in the heart and limbs.

scholarly journals Analysis of Mitochondrial Function and Localisation during Human Embryonic Stem Cell Differentiation In Vitro

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e52214 ◽  
Author(s):  
Andrew B. J. Prowse ◽  
Fenny Chong ◽  
David A. Elliott ◽  
Andrew G. Elefanty ◽  
Edouard G. Stanley ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Embryonic Stem Cell ◽  
Mitochondrial Function ◽  
Human Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation

scholarly journals Extracellular Matrix and Integrins in Embryonic Stem Cell Differentiation

2015 ◽  
Vol 8s2 ◽  
pp. BCI.S30377 ◽  
Author(s):  
Han Wang ◽  
Xie Luo ◽  
Jake Leighton
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Beta Cells ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
In Vitro Differentiation ◽  
Integrin Receptors

Embryonic stem cells (ESCs) are pluripotent cells with great therapeutic potentials. The in vitro differentiation of ESC was designed by recapitulating embryogenesis. Significant progress has been made to improve the in vitro differentiation protocols by toning soluble maintenance factors. However, more robust methods for lineage-specific differentiation and maturation are still under development. Considering the complexity of in vivo embryogenesis environment, extracellular matrix (ECM) cues should be considered besides growth factor cues. ECM proteins bind to cells and act as ligands of integrin receptors on cell surfaces. Here, we summarize the role of the ECM and integrins in the formation of three germ layer progenies. Various ECM–integrin interactions were found, facilitating differentiation toward definitive endoderm, hepatocyte-like cells, pancreatic beta cells, early mesodermal progenitors, cardiomyocytes, neuroectoderm lineages, and epidermal cells, such as keratinocytes and melanocytes. In the future, ECM combinations for the optimal ESC differentiation environment will require substantial study.

Specific Effect of 5-Fluorouracil on α-Fetoprotein Gene Expression During the In Vitro Mouse Embryonic Stem Cell Differentiation

2010 ◽  
Vol 29 (3) ◽  
pp. 297-304 ◽  
Author(s):  
David Pamies ◽  
Néstor Vicente-Salar ◽  
Miguel A. Sogorb ◽  
Enrique Roche ◽  
Juan A. Reig
Keyword(s):  
Es Cells ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryoid Bodies ◽  
Screening Methods ◽  
Embryonic Stem Cell Differentiation ◽  
Visceral Endoderm ◽  
Gene Markers ◽  
Wide Range

Embryonic stem (ES) cells are considered an important alternative to develop in vitro screening methods for embryotoxicity. Mouse ES cells can be cultured as cell suspension aggregates termed “embryoid bodies” (EBs) in which cells start to differentiate. We have studied the expression of several genes in the presence of a wide range of concentrations of 5-fluorouracil (5-FU). This well-established embryotoxic compound completely inhibited cell viability at 200 nmol/L in monolayer cultures. At lower concentrations, 5-FU led to decrease in the expression of the α-fetoprotein gene, a marker of the visceral endoderm, in the EBs. However, the expression of several mesodermal gene markers was not significantly affected at these concentrations. These results suggest a high sensitivity of the visceral endoderm differentiation to 5-FU. Therefore, the quantification of the α-fetoprotein gene after exposure to potential embryotoxicants should be considered an additional end point in future embryotoxicity assays in vitro with ES cells.

Hemangioblast development and regulation

1998 ◽  
Vol 76 (6) ◽  
pp. 947-956 ◽  
Author(s):  
Kyunghee Choi
Keyword(s):  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Cell Lineages ◽  
Cellular Events ◽  
New Information ◽  
In Vitro Systems ◽  
Inducing Factors ◽  
Mesoderm Inducing Factors

Hematopoietic and endothelial cell lineages are the first to mature from mesoderm in the developing embryo. However, little is known about the molecular and (or) cellular events leading to hematopoietic commitment. The recent applications of technology utilizing gene targeted mice and the employment of many available in vitro systems have facilitated our understanding of hematopoietic establishment in the developing embryo. It is becoming clear that embryonic hematopoiesis occurs both in the extra-embryonic yolk sac and within the embryo proper in the mouse. The existence of the long pursued hemangioblast, a common progenitor of hematopoietic and endothelial cells, is now formally demonstrated. Based on this new information, many studies are being conducted to understand hematopoietic commitment events from mesoderm. In this review, we will first discuss the establishment of the hematopoietic system with special emphasis on the most primitive hematopoietic committed cells, the hemangioblast. We will then discuss mesoderm-inducing factors and their possible role in hematopoietic lineage commitment.Key words: hematopoietic commitment, hemangioblast, in vitro embryonic stem cell differentiation.

scholarly journals Mouse lysocardiolipin acyltransferase controls the development of hematopoietic and endothelial lineages during in vitro embryonic stem-cell differentiation

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3601-3609 ◽  
Author(s):  
Chengyan Wang ◽  
Patrick W. Faloon ◽  
Zhijia Tan ◽  
Yaxin Lv ◽  
Pengbo Zhang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryoid Bodies ◽  
Embryonic Stem Cell Differentiation ◽  
Hematopoietic Stem ◽  
Endothelial Genes

Abstract The blast colony-forming cell (BL-CFC) was identified as an equivalent to the hemangioblast during in vitro embryonic stem (ES) cell differentiation. However, the molecular mechanisms underlying the generation of the BL-CFC remain largely unknown. Here we report the isolation of mouse lysocardiolipin acyltransferase (Lycat) based on homology to zebrafish lycat, a candidate gene for the cloche locus. Mouse Lycat is expressed in hematopoietic organs and is enriched in the Lin−C-Kit+Sca-1+ hematopoietic stem cells in bone marrow and in the Flk1+/hCD4+(Scl+) hemangioblast population in embryoid bodies. The forced Lycat transgene leads to increased messenger RNA expression of hematopoietic and endothelial genes as well as increased blast colonies and their progenies, endothelial and hematopoietic lineages. The Lycat small interfering RNA transgene leads to a decrease expression of hematopoietic and endothelial genes. An unbiased genomewide microarray analysis further substantiates that the forced Lycat transgene specifically up-regulates a set of genes related to hemangioblasts and hematopoietic and endothelial lineages. Therefore, mouse Lycat plays an important role in the early specification of hematopoietic and endothelial cells, probably acting at the level of the hemangioblast.

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