Research Description
Neural Specification of Pluripotent Stem Cells
Our laboratory intends to address how functionally diversified neuronal and glial subtypes are born in the making of our human brain. We have developed models of neural differentiation from mouse, monkey, and human pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In these in vitro models, neural differentiation recapitulates key events that occur in early embryo development, including induction of multipotential neuroepithelial cells that form neural tube-like structures, patterning of region-specific neural progenitors, and generation of neurons and glia with particular transmitter or functional phenotypes. In parallel, we are building transgenic human stem cell lines with regulatable gene expression. Together, we are dissecting biochemical interactions underlying the cellular differentiation processes under defined conditions. Such studies will hopefully bridge what we have learned from animal studies to human biology.
With the understanding of transcriptional and epigenetic regulation of subtype neural specification and discovery of neuroectoderm-determining factors, we are attempting to re-pattern or re-program specialized neural cells to needed cell types. This exploration will hopefully lead to the repair of injured or diseased brain by endogenous cells.
By introducing disease-provoking genes into ESCs or by activating the pluoripotent state of genetically mutated adult cells such as those from spinal muscular atrophy, ALS, Parkinson's disease, and leukodystrophy patients, we are creating model systems in which cellular and molecular pathological processes may be analyzed in bona fide human neurons and glia in a simplified environment. Such systems may be transformed to templates for discovering pharmaceuticals for treating these devastating neurological conditions.
The specialized neural cells produced from normal human stem cells in our laboratory are being tested for their therapeutic potential in animal models of neurological diseases such as Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Our long-term goal is to translate this technology to the re-building of our injured or diseased brain.
Recent Publications:
Li XJ, Du ZW, Zarnowska ED, Pankratz M, Hansen LO, Pearce RA, Zhang SC (2005): Specification of motoneurons from human embryonic stem cells. Nature Biotechnology., 23: 215-221
Yan Y, Yang, DL, Zarnowska ED, Du ZW, Valliere C, Pearce RA, Thomson JA, Zhang SC (2005): Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells, 23: 781-790.
Krencik R, Zhang SC (2006): Stem cell neural differentiation: a model for chemical biology. Current Opinion in Chemical Biology, 10: 592-597.
Johnson M.A., Weick J., Pearce, R., Zhang SC (2007): Functional neural development of human embryonic stem cells: Accelerated synaptic activity via astrocyte co-culture. Journal of Neuroscience, 27:3069-3077.
Pankratz MT, Li XJ, Lavaute TM, Lyons EA, Chen X, Zhang SC (2007) Directed neural differentiation of human embryonic stem cells via an obligated primitive anterior stage. Stem Cells 25: 1511-1520.
Yang D, Zhang Z, Oldenburg M, Ayala M, Zhang SC (2008): Human ES cell-derived dopamine neurons reverse functional deficit in a Parkinson's rat. Stem Cells, 26: 55-63 (online, Oct 18, 2007).
Du, Z.W., Hu, B.Y., Sauer, B., Zhang, SC. (2009) Master Human ESC Lines For Versatile Transgenic Modification By Recombination Mediated Cassette Exchange. Stem Cells, 27:1032-1041.
Hu, B., Du, Z.W., Li, X.J., Ayala, M., Zhang, SC. (2009) Oligodendrocytes from human embryonic stem cells: Conserved transcription networks and divergent FGF effects. Development, 136:1443-1452.
LaVaute, T.M., Yoo Y., Pankratz, M.T., Weick JP, Zhang, SC. (2009) Regulation of neural specification from human ESCs by BMP and FGF. Stem Cells, 27:1741-49.
Li XJ, Zhang X, Johnson MA, Wang ZB, Lavaute TM, Zhang SC (2009): Coordination of Sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development, online.
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