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BIOLOGICAL SCIENCES / DEVELOPMENTAL BIOLOGY

Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells

Maya Schuldiner^*, Ofra Yanuka^*, Joseph Itskovitz-Eldor, Douglas A. Melton^,, and Nissim Benvenisty^*,

^*Department of Genetics, The Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel; Department of Obstetrics and Gynecology, Rambam Medical Center, Faculty of Medicine, The Technion, Haifa 31096, Israel; and Department of Molecular and Cellular Biology, Howard Hughes Medical Institute, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138

Contributed by Douglas A. Melton

Accepted for publication August 8, 2000.

Abstract: Human embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of in vitro fertilized human blastocysts. We examined the potential of eight growth factors [basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGF-β1), activin-A, bone morphogenic protein 4 (BMP-4), hepatocyte growth factor (HGF), epidermal growth factor (EGF), β nerve growth factor (βNGF), and retinoic acid] to direct the differentiation of human ES-derived cells in vitro. We show that human ES cells that have initiated development as aggregates (embryoid bodies) express a receptor for each of these factors, and that their effects are evident by differentiation into cells with different epithelial or mesenchymal morphologies. Differentiation of the cells was assayed by expression of 24 cell-specific molecular markers that cover all embryonic germ layers and 11 different tissues. Each growth factor has a unique effect that may result from directed differentiation and/or cell selection, and we can divide the overall effects of the factors into three categories: growth factors (Activin-A and TGFβ1) that mainly induce mesodermal cells; factors (retinoic acid, EGF, BMP-4, and bFGF) that activate ectodermal and mesodermal markers; and factors (NGF and HGF) that allow differentiation into the three embryonic germ layers, including endoderm. None of the growth factors directs differentiation exclusively to one cell type. This analysis sets the stage for directing differentiation of human ES cells in culture and indicates that multiple human cell types may be enriched in vitro by specific factors.

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To whom reprint requests should be addressed. E-mail: dmelton{at}biohp.harvard.edu or nissimb{at}mail.ls.huji.ac.il.

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Insulin Production by Human Embryonic Stem Cells.

S. Assady, G. Maor, M. Amit, J. Itskovitz-Eldor, K. L. Skorecki, and M. Tzukerman (2001)
Diabetes 50, 1691-1697
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Stem Cells: A Journey into a New Frontier.

B. E. PETERSEN and N. TERADA (2001)
J. Am. Soc. Nephrol. 12, 1773-1780
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Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines.

J. Nichols, I. Chambers, T. Taga, and A. Smith (2001)
Development 128, 2333-2339
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Differentiation of Embryonic Stem Cells to Insulin-Secreting Structures Similar to Pancreatic Islets.

N. Lumelsky, O. Blondel, P. Laeng, I. Velasco, R. Ravin, and R. McKay (2001)
Science 292, 1389-1394
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An efficient system for conditional gene expression in embryonic stem cells and in their in vitro and in vivo differentiated derivatives.

L. Vallier, J. Mancip, S. Markossian, A. Lukaszewicz, C. Dehay, D. Metzger, P. Chambon, J. Samarut, and P. Savatier (2001)
PNAS 98, 2467-2472
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Intercellular signals regulating pancreas development and function.

S. K. Kim and M. Hebrok (2001)
Genes & Dev. 15, 111-127
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Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro.

M. J. Shamblott, J. Axelman, J. W. Littlefield, P. D. Blumenthal, G. R. Huggins, Y. Cui, L. Cheng, and J. D. Gearhart (2001)
PNAS 98, 113-118
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Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro.

M. J. Shamblott, J. Axelman, J. W. Littlefield, P. D. Blumenthal, G. R. Huggins, Y. Cui, L. Cheng, and J. D. Gearhart (2000)
PNAS
 |  Abstract »  |  Full Text »

Differentiation of Embryonic Stem Cells to Insulin-Secreting Structures Similar to Pancreatic Islets.

N. Lumelsky, O. Blondel, P. Laeng, I. Velasco, R. Ravin, and R. McKay (2001)
Science 292, 1389-1394
 |  Abstract »  |  Full Text »

Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro.

M. J. Shamblott, J. Axelman, J. W. Littlefield, P. D. Blumenthal, G. R. Huggins, Y. Cui, L. Cheng, and J. D. Gearhart (2000)
PNAS
 |  Abstract »  |  Full Text »

An efficient system for conditional gene expression in embryonic stem cells and in their in vitro and in vivo differentiated derivatives.

L. Vallier, J. Mancip, S. Markossian, A. Lukaszewicz, C. Dehay, D. Metzger, P. Chambon, J. Samarut, and P. Savatier (2001)
PNAS 98, 2467-2472
 |  Abstract »  |  Full Text »  |  PDF »

Hematopoietic colony-forming cells derived from human embryonic stem cells.

D. S. Kaufman, E. T. Hanson, R. L. Lewis, R. Auerbach, and J. A. Thomson (2001)
PNAS 98, 10716-10721
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