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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.
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Submitted March 29, 2007
Accepted August 16, 2007
Self-renewal of human embryonic stem cells requires insulin-like growth factor-1 receptor and ERBB2 receptor signaling
Linlin Wang, Thomas C Schulz, Eric S Sherrer, Derek S Dauphin, Soojung Shin, Angelique M Nelson, Carol B Ware, Mei Zhan, Chao-Zhong Song, Xiaoji Chen, Sandii N Brimble, Amanda McLean, Maria J. Galeano, Elizabeth W Uhl, Kevin A. D'Amour, Jonathan D Chesnut, Mahendra S Rao, C. Anthony Blau*, and Allan J Robins
Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, United States
Novocell, Inc., Athens, GA, United States
Invitrogen Corporation, Carlsbad, CA, United States
Department of Comparative Medicine, University of Washington, Seattle, WA, United States
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, United States
Department of Animal and Dairy Science, The University of Georgia, Athens, GA, United States
Department of Pathology, College of Veterinary Medicine, The University of Georgia, Athens, GA, United States
Novocell, Inc., San Diego, CA, United States
* Corresponding author; email: tblau{at}u.washington.edu.
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 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 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 and was attributable to high concentrations of insulin in the proprietary KnockOut Serum Replacer (KSRTM). 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 analogue, heregulin1 (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 media for the growth and maintenance of pluripotent hESCs.
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[Abstract]
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