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Blood, 1 December 2007, Vol. 110, No. 12, pp. 4111-4119. Prepublished online as a Blood First Edition Paper on August 29, 2007; DOI 10.1182/blood-2007-03-082586. This Article Full Text Full Text (PDF) Supplemental Methods and Tables Supplemental Figures All Versions of this Article: blood-2007-03-082586v1 110/12/4111    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wang, L. Articles by Robins, A. J. Search for Related Content PubMed PubMed Citation Articles by Wang, L. Articles by Robins, A. J. Related Collections Hematopoiesis and Stem Cells Signal Transduction Stem Cells in Hematology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  STEM CELLS IN HEMATOLOGY Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling Linlin Wang1, Thomas C. Schulz2, Eric S. Sherrer2, Derek S. Dauphin1, Soojung Shin3, Angelique M. Nelson4, Carol B. Ware4, Mei Zhan5, Chao-Zhong Song5, Xiaoji Chen1, Sandii N. Brimble2, Amanda McLean6, Maria J. Galeano2, Elizabeth W. Uhl7, Kevin A. D'Amour8, Jonathan D. Chesnut3, Mahendra S. Rao3, C. Anthony Blau1, and Allan J. Robins2 1 Division of Hematology, Department of Medicine, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle; 2 Novocell, Athens, GA; 3 Invitrogen, Carlsbad, CA; 4 Department of Comparative Medicine, University of Washington, Seattle; 5 Division of Medical Genetics, Department of Medicine, University of Washington, Seattle; 6 Department of Animal and Dairy Science, University of Georgia, Athens; 7 Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens; and 8 Novocell, San Diego, CA Despite progress in developing defined conditions for human embryonic stem cell (hESC) cultures, little is known about the cell-surface receptors that are activated under conditions supportive of hESC self-renewal. A simultaneous interrogation of 42 receptor tyrosine kinases (RTKs) in hESCs following stimulation with mouse embryonic fibroblast (MEF) conditioned medium (CM) revealed rapid and prominent tyrosine phosphorylation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R); less prominent tyrosine phosphorylation of epidermal growth factor receptor (EGFR) family members, including ERBB2 and ERBB3; and trace phosphorylation of fibroblast growth factor receptors. Intense IGF1R and IR phosphorylation occurred in the absence of MEF conditioning (NCM) and was attributable to high concentrations of insulin in the proprietary KnockOut Serum Replacer (KSR). Inhibition of IGF1R using a blocking antibody or lentivirus-delivered shRNA reduced hESC self-renewal and promoted differentiation, while disruption of ERBB2 signaling with the selective inhibitor AG825 severely inhibited hESC proliferation and promoted apoptosis. A simple defined medium containing an IGF1 analog, heregulin-1β (a ligand for ERBB2/ERBB3), fibroblast growth factor-2 (FGF2), and activin A supported long-term growth of multiple hESC lines. These studies identify previously unappreciated RTKs that support hESC proliferation and self-renewal, and provide a rationally designed medium for the growth and maintenance of pluripotent hESCs. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. A. Prokhorova, K. T. G. Rigbolt, P. T. Johansen, J. Henningsen, I. Kratchmarova, M. Kassem, and B. Blagoev Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Quantitative Comparison of the Membrane Proteomes of Self-renewing and Differentiating Human Embryonic Stem Cells Mol. Cell. Proteomics, May 1, 2009; 8(5): 959 - 970. [Abstract] [Full Text] [PDF] J.-Y. Yu, S. H. Reynolds, S. D. Hatfield, H. R. Shcherbata, K. A. Fischer, E. J. Ward, D. Long, Y. 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Meldrum Neonatal stem cells exhibit specific characteristics in function, proliferation, and cellular signaling that distinguish them from their adult counterparts Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1491 - R1497. [Abstract] [Full Text] [PDF]

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