Hao Wu, Jun Xu , Zhiping P. Pang, Weihong Ge, Kevin J. Kim, Bruno Blanchi, Caifu Chen, Thomas C. Südhof , and Yi E. Sun: Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines, Proc. Natl. Acad. Sci. (PNAS) , 10.1073/pnas.0706199104 and August 10, 2007, August 21, 2007, vol. 104, no. 34: 13821–13826.
The self-renewal and differentiation potential of human embryonic stem cells (hESCs) suggests that hESCs could be used for regenerative medicine, especially for restoring neuronal functions in brain diseases. However, the functional properties of neurons derived from hESC are largely unknown. Moreover, because hESCs were derived under diverse conditions, the possibility arises that neurons derived from different hESC lines exhibit distinct properties, but this possibility remains unexplored. To address these issues, we developed a protocol that allows stepwise generation from hESCs of cultures composed of 70–80% human neurons that exhibit spontaneous synaptic network activity. Comparison of neurons derived from the well characterized HSF1 and HSF6 hESC lines revealed that HSF1- but not HSF6-derived neurons exhibit forebrain properties. Accordingly, HSF1-derived neurons initially form primarily GABAergic synaptic networks, whereas HSF6-derived neurons initially form glutamatergic networks. microRNA profiling revealed significant expression differences between the two hESC lines, suggesting that microRNAs may influence their distinct differentiation properties. These observations indicate that although both HSF1 and HSF6 hESCs differentiate into functional neurons, the two hESC lines exhibit distinct differentiation potentials, suggesting that they are preprogrammed. Information on hESC line-specific differentiation biases is crucial for neural stem cell therapy and establishment of novel disease models using hESCs. See the complete article at PNAS.

Matthias Groszer, Rebecca Erickson, Deirdre D. Scripture-Adams, Joseph D. Dougherty, Janel Le Belle, Jerome A. Zack, Daniel H. Geschwind, Xin Liu, Harley I. Kornblum, and Hong Wu: PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry
PNAS, January 3, 2006, v103, n1: 111-116. 
Previous studies have demonstrated that a small subpopulation of brain tumor cells share key characteristics with neural stem/progenitor cells in terms of phenotype and behavior. These findings suggest that brain tumors might contain "cancer stem cells" that are critical for tumor growth. However, the molecular pathways governing such stem cell-like behavior remain largely elusive. Our previous study suggests that the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) tumor suppressor gene, one of the most frequently mutated genes in glioblastomas, restricts neural stem/progenitor cell proliferation in vivo. In the present study, we sought to determine the role of PTEN in long-term maintenance of stem cell-like properties, cell cycle entry and progression, and growth factor dependence and gene expression. Our results demonstrate an enhanced self-renewal capacity and G0-G1 cell cycle entry and decreased growth factor dependency of Pten null neural/stem progenitor cells. Therefore, loss of PTEN leads to cell physiological changes, which collectively are sufficient to increase the pool of self-renewing neural stem cells and promote their escape from the homeostatic mechanisms of proliferation control. See the complete article at PNAS.

Yin Shen, Janet Chow, Zunde Wang, and Guoping Fan: Abnormal CpG Island Methylation Occurs During in vitro Differentiation of Human Embryonic Stem Cells
Human Molecular Genetics, 2006, v15, n17
ISCBM scientists found that neural stem cells grown from one of the federally approved human embryonic stem cell lines proved to be inferior to neural stem cells derived from fetal tissue donated for research. Dr. Guoping Fan and associates coaxed cells from the federally approved line to differentiate into neural stem cells, a process that might one day be used to grow replacement cells to treat such debilitating  diseases as Parkinson’s and Alzheimer’s. However, the neural stem cells had an abnormality in a gene called CPT 1A that inhibited expression, a metabolic condition that causes hypoglycemia in humans.The study appears this week in an early online edition of the journal Human Molecular Genetics

Title: A novel model of Rett Syndrome using human ES cells

Principal Investigator: Yi E. Sun, PhD

Sponsor: Stem Cell Research Foundation

Genetic links between gene mutations and various debilitating neurological disorders including Parkinson’s and Alzheimer’s diseases have been discovered. Two extreme cases are Huntington’s disease and Rett syndrome, whereby more than 80% of the patients carry mutations in the disease genes, Huntingtin and Mecp2, respectively. These discoveries allowed scientists to generate mouse models by introducing genetic mutations to study the diseases. However, in most cases, while the mouse model resembles certain aspects of the human disease, clear differences between the model and the disease can be readily observed. In fact, many drugs tested to be effective in mouse models turn out to be ineffective in humans. This has led to uncertainty about the approach of using mouse models for drug screening or therapeutic testing. We hypothesize that pluripotent human embryonic stem cells (hESCs) can be modified to produce diseased neurons, and this system can be readily used to model for various neurological diseases. In addition, such a system can also be used for drug screening. As a proof of principle, we propose to genetically manipulate hESCs and build a human ex vivo neuronal model for a neurodevelopmental disorder, Rett syndrome.