Human embryonic stem (ES) cells not only provide a continuous cell source for potential cell therapy but also offer an otherwise inaccessible system to unveil events of early embryonic development in man. This proposal will examine how the earliest neural cells, neuroepithelia, are specified from the naive ES cells, and test the hypothesis that neural specification in humans employs a similar mechanism as in vertebrate animals. We will first re-create in culture the developmental events of the first 2-3 weeks of human embryonic development during which ES cells (NIH Registry WA01 and WA09) will be differentiated through stages of embryoid bodies, primitive ectoderm-like cells, neural tube-like rosette ceils until the neural precursor cell stage. The stage-specific events will be defined by DNA microarray analysis along with the characteristic morphologic changes. Using this stepwise differentiation culture model system, we will then examine neural- inducing and inhibitory factors on neural specification from human ES cells. The identity of ES cell-derived neural precursors will be determined by the differentiated progenies of clonally derived cells in vitro and in vivo. The function of the in vitro generated mature neural cells will be assessed using electrophysiological techniques to measure action potentials and synaptic communication in neurons in culture and after transplantation into mouse brains. This study will lead to an optimized procedure for generating enriched or purified neural precursor cells, which will lay the groundwork for potential future use of human ES cells in the treatment of neurological injuries and diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS045926-01
Application #
6599861
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Chiu, Arlene Y
Project Start
2003-02-01
Project End
2008-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$337,339
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Huang, Cindy Tzu-Ling; Tao, Yunlong; Lu, Jianfeng et al. (2016) Time-Course Gene Expression Profiling Reveals a Novel Role of Non-Canonical WNT Signaling During Neural Induction. Sci Rep 6:32600
Tao, Yunlong; Zhang, Su-Chun (2016) Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell 19:573-586
Lu, Jianfeng; Zhong, Xuefei; Liu, Huisheng et al. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34:89-94
Chen, Yuejun; Xiong, Man; Dong, Yi et al. (2016) Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease. Cell Stem Cell 18:817-26
Jones, Jeffrey R; Zhang, Su-Chun (2016) Engineering human cells and tissues through pluripotent stem cells. Curr Opin Biotechnol 40:133-138
Chen, Yuejun; Cao, Jingyuan; Xiong, Man et al. (2015) Engineering Human Stem Cell Lines with Inducible Gene Knockout using CRISPR/Cas9. Cell Stem Cell 17:233-44
Du, Zhong-Wei; Chen, Hong; Liu, Huisheng et al. (2015) Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat Commun 6:6626
Chen, Hong; Qian, Kun; Chen, Wei et al. (2015) Human-derived neural progenitors functionally replace astrocytes in adult mice. J Clin Invest 125:1033-42
Liu, Huisheng; Lu, Jianfeng; Chen, Hong et al. (2015) Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability. Sci Rep 5:12189
Qian, Kun; Huang, Cindy Tzu-Ling; Huang, CindyTzu-Ling et al. (2014) A simple and efficient system for regulating gene expression in human pluripotent stem cells and derivatives. Stem Cells 32:1230-8

Showing the most recent 10 out of 60 publications