Neurotrophins mediate human embryonic stem cell survival
April D Pyle1, Leslie F Lock2, 3 & Peter J Donovan1, 3
1 Germ Cell and Stem Cell Group, Stem Cell Biology Program, Institute for Cell Engineering, Johns Hopkins University, School of Medicine, Broadway Research Building, Suite 759, 733 North Broadway, Baltimore, Maryland 21205, USA.
2 Genetic Models Group, Stem Cell Biology Program, Institute for Cell Engineering, Johns Hopkins University, School of Medicine, Broadway Research Building, Suite 759, 733 North Broadway, Baltimore, Maryland 21205, USA.
3 Present address: Stem Cell Program and Departments of Developmental and Cell Biology and of Biological Chemistry, Hewitt Hall, University of California, Irvine, Irvine, California 92697, USA.
Growth of human embryonic stem (hES) cells as a pluripotent population requires a balance between survival, proliferation and self-renewal signals. Here we demonstrate that hES cells express receptors of the tropomyosin-related kinase (TRK) family, which mediate antiapoptotic signals. We show that three TRK ligands, brain-derived neurotrophic factor, neurotrophin 3 and neurotrophin 4, are survival factors for hES cells. Addition of neurotrophins to hES cell cultures effects a 36-fold improvement in their clonal survival. hES cell cultures maintained in medium containing neurotrophins remain diploid and retain full developmental potency. In the presence of neurotrophins, TRK receptors in hES cells are phosphorylated; TRK receptor inhibition leads to hES cell apoptosis. The survival activity of neurotrophins in hES cells is mediated by the phosphatidylinositol-3-kinase pathway but not the mitogen-activated protein kinase pathway. Neurotrophins improve hES cell survival and may facilitate their manipulation and the development of high-throughput screens to identify factors responsible for hES cell differentiation.
