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One or more keywords matched the following properties of Duncan, Stephen
keywords stem cells
overview Research in the Duncan laboratory focuses on liver development and disease using mice and induced pluripotent stem cells (iPSCs) as model systems. 1) Molecular mechanisms underlying liver development Development of a simple two-cell embryo to a complex multicellular organism is a highly dynamic procedure requiring orchestrated cell movements and multiple interactions between cells and their surroundings. As cells differentiate, not only do they receive extra-cellular signals they secrete and display signals of their own, thereby defining the makeup of their local environments. The result of these intercellular communications is the controlled differentiation of populations of progenitor cells to produce novel cell types. The repertoire of genes expressed by the cell defines the phenotype. Gene transcription therefore plays a critical role in regulating cell fate. To comprehend the molecular mechanisms controlling embryonic development my laboratory is, therefore, attempting to understand how transcription factors interact with extracellular signaling mechanisms to drive cell differentiation. Most organs are a complex array of different cell types and tissues, all of which dynamically interact to regulate organogenesis. Tissue complexity can make it challenging to measure the contribution of a specific transcription factor to overall organ or tissue development. However, the liver, in which 80% of the cells are hepatocytes, offers an attractive and relatively simple system in which to study the role of transcription factors during morphogenesis and development. In the laboratory, we use transgenic and knockout mice and genetically modified iPSCs to uncover the mechanisms through which transcription factors and cell signaling molecules are required to drive liver development. 2) Using pluripotent stem cells to study inborn errors of hepatic metabolism The liver has vital endocrine and exocrine functions that regulate a diverse array of metabolic activities. Although specific forms of inborn errors of hepatic metabolism are relatively rare, cumulatively they are common and without treatment are often fatal. To date, a liver transplant can treat the most severe hepatic metabolic deficiencies. Unfortunately, the number of available donor livers is limited, and demand for transplant-quality livers continues to increase. With donor livers being scarce, it has been proposed that cell transplant therapy may offer an alternative to an organ transplant. One source of hepatocytes for transplant could be human iPSCs. Several projects in the laboratory, therefore, focus on generating functional hepatocytes from iPSCs. Metabolic liver disease can also often be treated using small molecules or biologics that, in general, have an established track record of success. With this in mind, we are developing a platform that will facilitate the efficient identification of treatments for rare inborn errors of hepatic metabolism. We propose to 1) establish human pluripotent stem cells harboring genetic variants associated with disease in patients, 2) differentiate the stem cells to hepatocytes and examine whether genetic variations recapitulate the disease in culture, 3) establish assays that are compatible with moderate to high throughput screening to identify existing drugs that could be repurposed to correct the pathophysiology of the disease, and 4) establish the efficacy and safety of lead drugs using humanized animal models and human trials.
One or more keywords matched the following items that are connected to Duncan, Stephen
Item TypeName
Concept Multipotent Stem Cells
Concept Stem Cells
Concept Colony-Forming Units Assay
Concept Hematopoietic Stem Cells
Concept Induced Pluripotent Stem Cells
Concept Stem Cell Transplantation
Concept Embryonic Stem Cells
Concept Pluripotent Stem Cells
Academic Article Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner.
Academic Article Aneuploidy is permissive for hepatocyte-like cell differentiation from human induced pluripotent stem cells.
Academic Article Differentiation of hepatocytes from pluripotent stem cells.
Academic Article Engineering liver tissue from induced pluripotent stem cells: a first step in generating new organs for transplantation?
Academic Article Identification of small molecules for human hepatocyte expansion and iPS differentiation.
Academic Article Hepatocyte-like cells differentiated from human induced pluripotent stem cells: relevance to cellular therapies.
Academic Article Comparison of cardiomyogenic potential among human ESC and iPSC lines.
Academic Article JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia.
Academic Article A cell surfaceome map for immunophenotyping and sorting pluripotent stem cells.
Academic Article Modeling hepatitis C virus infection using human induced pluripotent stem cells.
Academic Article HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells.
Academic Article Induction of cardiomyogenesis in human embryonic stem cells by human embryonic stem cell-derived definitive endoderm.
Academic Article Isoflurane preconditioning elicits competent endogenous mechanisms of protection from oxidative stress in cardiomyocytes derived from human embryonic stem cells.
Academic Article Generation of human induced pluripotent stem cells by simple transient transfection of plasmid DNA encoding reprogramming factors.
Academic Article Culture of human pluripotent stem cells using completely defined conditions on a recombinant E-cadherin substratum.
Academic Article Foxa1 functions as a pioneer transcription factor at transposable elements to activate Afp during differentiation of embryonic stem cells.
Academic Article Organogenesis and development of the liver.
Academic Article Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells.
Academic Article Design of the artificial acellular feeder layer for the efficient propagation of mouse embryonic stem cells.
Academic Article Development of the mammalian liver and ventral pancreas is dependent on GATA4.
Academic Article Improved cardiac function in infarcted mice after treatment with pluripotent embryonic stem cells.
Academic Article Generation of embryos directly from embryonic stem cells by tetraploid embryo complementation reveals a role for GATA factors in organogenesis.
Academic Article GATA6 is essential for embryonic development of the liver but dispensable for early heart formation.
Academic Article GATA4 is essential for formation of the proepicardium and regulates cardiogenesis.
Academic Article Gene targeting in the mouse: advances in introduction of transgenes into the genome by homologous recombination.
Academic Article Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation.
Academic Article An efficient method to successively introduce transgenes into a given genomic locus in the mouse.
Academic Article Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha.
Academic Article Regulation of a transcription factor network required for differentiation and metabolism.
Academic Article Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(-/-) embryos.
Academic Article Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells.
Academic Article Generation of iPSCs as a Pooled Culture Using Magnetic Activated Cell Sorting of Newly Reprogrammed Cells.
Academic Article Liver Capsule: Multipotent stem cells and their lineage restriction to hepatocytes.
Academic Article FGF2 mediates hepatic progenitor cell formation during human pluripotent stem cell differentiation by inducing the WNT antagonist NKD1.
Academic Article N-glycoprotein surfaceome of human induced pluripotent stem cell derived hepatic endoderm.
Academic Article Mapping the Cell-Surface N-Glycoproteome of Human Hepatocytes Reveals Markers for Selecting a Homogeneous Population of iPSC-Derived Hepatocytes.
Academic Article ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion.
Academic Article A small-molecule screen reveals that HSP90? promotes the conversion of induced pluripotent stem cell-derived endoderm to a hepatic fate and regulates HNF4A turnover.
Academic Article A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia.
Academic Article Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci.
Academic Article Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress.
Academic Article Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells.
Academic Article Using Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells for Drug Discovery.
Academic Article The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease.
Academic Article A Screen Using iPSC-Derived Hepatocytes Reveals NAD+ as a Potential Treatment for mtDNA Depletion Syndrome.
Academic Article HNF4A Regulates the Formation of Hepatic Progenitor Cells from Human iPSC-Derived Endoderm by Facilitating Efficient Recruitment of RNA Pol II.
Academic Article Generation of isogenic Propionyl-CoA carboxylase beta subunit (PCCB) deficient induced pluripotent stem cell lines.
Academic Article GATA6 defines endoderm fate by controlling chromatin accessibility during differentiation of human-induced pluripotent stem cells.
Academic Article Advancements in Disease Modeling and Drug Discovery Using iPSC-Derived Hepatocyte-like Cells.
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