Steenbock Professor of Behavioral and Neural Sciences - M.D. Wenzhou Medical College - Ph.D., University of Saskatchewan
Phone: (608) 265-2543 | Fax: (608) 262-9441
RESEARCH INTERESTS - Human Stem Cells and Neural Regeneration
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.
Over the past decade, we have demonstrated that neural differentiation from human ESCs follows similar fundamental programs that operate in vertebrate animals. We did identify unique transcriptional network orchestrated by a transcription factor PAX6 that determines the neuroectoderm fate in humans. We also found special utilization of common signaling pathways in specific lineage differentiation at a particular developmental stage. 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, a concept that is used for reprogramming somatic cells to iPSCs. This exploration will potentially 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 or direct neural conversion 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.
With the identification of the primitive neural stem cells, we have successfully directed human ESCs and iPSCs to regionally and functionally specialized neural cells, including cortical glutamatergic neurons, striatal medium spiny GABAergic neurons, basal forebrain cholinergic neurons, midbrain dopamine neurons, spinal motoneurons, oligodendrocytes, and region-specific astrocyte subtypes. 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 Huntington’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, brain/spinal cord injury, and multiple sclerosis. Our long-term goal is to translate our understanding of the regulatory machinery of human neural subtype generation to the re-building of our injured or diseased brain.
- Krencik,R., Weick J.H., Liu Y., Zhang,Z., and Zhang,S.C. (2011). Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nature Biotechnol., 29, 528-534. NIHMSID 297687
- Weick JP, Johnson MA, Skroch SP, Williams JC, Deisseroth K, Zhang SC (2010). Functional Control of Transplantable Human ESC-Derived Neurons Via Optogenetic Targeting. Stem Cells. 28, 2008-2016. PMCID:PMC 2988875
- Zhang X, Huang CT, Chen J, Pankratz MT, Xi J, Li J, Yang Y, LaVaute TM, Li XJ, Ayala M, Bondarenko GI, Z Du ZW, Jin Y, Golos TG, Zhang SC (2010): Pax6 Is a Human Neuroectoderm Cell Fate Determinant. Cell Stem Cell, 7: 90-100. PMCID: PMC2904346
- Hu B.Y., Weick J., Yu J. Zhang X.., Ma L., Thomson J.A., Zhang SC (2010): Neural Differentiation of Human Induced Pluripotent Stem Cells Follows Developmental Principles but with Variable Potency. Proc. Natl. Acad. Sci. USA, 107: 4335-4340. PMCID: PMC2840097
- Li XJ, Zhang X, Johnson MA, Wang ZB, Lavaute TM, Zhang S-C (2009): Coordination of Sonic hedgehog and Wnt signaling determines ventral and dorsal telencephalic neuron types from human embryonic stem cells. Development, 136:4055-4063. PMCID2778748
- 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. PMCID: PMC2789116
- 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, May;136(9):1443-52 PMCID: PMC2674255
- Du,Z.W., Hu,B.Y., Ayala,M., Sauer,B., and Zhang,S.C. (2009). Cre recombination-mediated cassette exchange for building versatile transgenic human embryonic stem cells lines. Stem Cells, 27:1032-1041. PMCID: PMC2801346
- Meyer JS, Shearer RL, Capowski EE, Wright LS, Wallace KA, McMillan EL, Zhang SC, Gamm DM. (2009) Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc. Natl. Acad. Sci. USA, 106: 16698-703. PMCID: PMC2757802
- Xia X, Ayala M, Thiede BR, Zhang SC (2008) In Vitro and In Vivo Induced Transgene Expression in Human Embryonic Stem Cells and Derivatives. Stem Cells, 26:525-533. PMCID: PMC2707826
- Yang D, Zhang Z, Oldenburg M, Ayala M, Zhang S-C (2008): Human ES cell-derived dopamine neurons reverse functional deficit in a Parkinson’s rat. Stem Cells, Jan;26(1):55-63 PMCID: PMC2707927
- 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 PMCID: PMC2735200
- Yan Y, Yang, DL, Zarnowska ED, Du ZW, Werbel, B., 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. PMCID: PMC2707939
- 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 PMCID: 15685164
- Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA (2001): In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nature Biotechnol., 19: 1129-1131. PMCID: 11731781