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Shuibing Chen,
Malgorzata Borowiak, Julia L Fox,
René Maehr,
Kenji Osafune,
Lance Davidow,
Kelvin Lam,
Lee F Peng,
Stuart L Schreiber,
Lee L Rubin,
Douglas Melton
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ABSTRACT: Stepwise differentiation from embryonic stem cells (ESCs) to functional insulin-secreting beta cells will identify key steps in beta-cell development and may yet prove useful for transplantation therapy for diabetics. An essential step in this schema is the generation of pancreatic progenitors--cells that express Pdx1 and produce all the cell types of the pancreas. High-content chemical screening identified a small molecule, (-)-indolactam V, that induces differentiation of a substantial number of Pdx1-expressing cells from human ESCs. The Pdx1-expressing cells express other pancreatic markers and contribute to endocrine, exocrine and duct cells, in vitro and in vivo. Further analyses showed that (-)-indolactam V works specifically at one stage of pancreatic development, inducing pancreatic progenitors from definitive endoderm. This study describes a chemical screening platform to investigate human ESC differentiation and demonstrates the generation of a cell population that is a key milepost on the path to making beta cells.
Nature Chemical Biology 05/2009; 5(4):258-65. · 14.69 Impact Factor
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ABSTRACT: An essential step for therapeutic and research applications of stem cells is the ability to differentiate them into specific cell types. Endodermal cell derivatives, including lung, liver, and pancreas, are of interest for regenerative medicine, but efforts to produce these cells have been met with only modest success. In a screen of 4000 compounds, two cell-permeable small molecules were indentified that direct differentiation of ESCs into the endodermal lineage. These compounds induce nearly 80% of ESCs to form definitive endoderm, a higher efficiency than that achieved by Activin A or Nodal, commonly used protein inducers of endoderm. The chemically induced endoderm expresses multiple endodermal markers, can participate in normal development when injected into developing embryos, and can form pancreatic progenitors. The application of small molecules to differentiate mouse and human ESCs into endoderm represents a step toward achieving a reproducible and efficient production of desired ESC derivatives.
Cell stem cell 05/2009; 4(4):348-58. · 23.56 Impact Factor
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Benjamin Z Stanton,
Lee F Peng,
Nicole Maloof,
Kazuo Nakai,
Xiang Wang,
Jay L Duffner,
Kennedy M Taveras,
Joel M Hyman,
Sam W Lee,
Angela N Koehler,
James K Chen, Julia L Fox,
Anna Mandinova,
Stuart L Schreiber
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ABSTRACT: Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.
Nature Chemical Biology 01/2009; 5(3):154-156. · 14.69 Impact Factor
