Faculty: Su-Chun Zhang (MD/PhD)
|Dept:||Professor, Neuroscience and Neurology
Molecular and Cellular Pharmacology Program
Our laboratory focuses on addressing how functionally diversified neuronal and glial subtypes are born in the building and rebuilding of our human brain. Over the past decade, 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). By following the developmental principles, we have successfully directed hPSCs 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. We have also discovered regulatory mechanisms that are quite unique to human neural development, including the identification of Pax6 as a transcriptional determinant of the neuroectoderm. We are currently dissecting the transcriptional and epigenetic regulation of neuroectodermal induction and neural subtype specification. Information learned from these studies sets up the foundation for us to switch or re-program neural cell types.
Building upon our success in directed neural differentiation, we are establishing iPSCs and reprogramming neural cells from skin tissues of patients with neurological disorders, focusing on motor neuron diseases (ALS, SMA), Huntington’s disease, Down syndrome and Alzheimer’s disease. We are now dissecting cellular and molecular processes that underlie the neural degeneration. We have also established the state-of-the-art gene editing technology to build reporter and transgenic disease human cell lines. We are transforming these cellular models to templates for drug discovery.
In the process of functional analysis of hPSC-derived neuronal and glial cells in animal models of neurological diseases, we discovered that appropriately specified neurons project to correct brain regions and connect to the right target neurons in the adult mouse brain, suggesting a surprisingly regenerative capacity of human stem cell-produced neurons, very much like those born during embryonic development. We are currently evaluating the therapeutic potential of human stem cell generated midbrain dopamine neurons, striatal medium spiny GABA neurons, and spinal astrocytes in animal (including non-human primate) models of Parkinson’s disease, Huntington’s disease, and motor neuron diseases, respectively. With the understanding of the regulatory process of human neural programming and reprogramming, our long-term goal is to rebuild our aging or diseased brain from within.
Laboratory Website: http://www.waisman.wisc.edu/scrp/zhang.html
- Liu Y, Weick JP, Liu H, Krencik R, ZHang X, Ma L, Zhou GM, Ayala M, Zhang SC. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol. 2013 Apr 21. doi: 10.1038/nbt.2565. [Epub ahead of print] PMID: 23604284
- Emborg ME, Zhang Z, Joers V, Brunner K, Bondarenko V, Ohshima S, Zhang SC. Intracerebral transplantation of differentiated human embyronic stem cells to hemiparkinsonian monkeys. Cell Transplant. 2013;22(5):831-8. doi: 10.3727/096368912X647144. PMID: 23594934
- Emborg ME, Liu Y, Xi J, Zhang X, Yin Y, Lu J, Joers V, Swanson C, Holden JE, Zhang SC. Induced pluripotent stem cell-derived neural cells survive and mature in the the nonhuman primate brain. Cell Rep. 2013 Mar 28;3(3);646-50. doi: 10.1016/j.celrep.2013.02.016. Epub 2013 Mar 14. PMID: 23499447
- Emborg ME, Zhang Z, Joers V, Brunner K, Bondarenko V, Ohshima S, Zhang SC. Intracerebral Transplantation of Differentiated Human Embryonic Stem Cells to Hemiparkinsonian Monkeys. Cell Transplant. 2012 Jun 15. doi: 10.3727/096368912X47144. [Epub ahead of print] PMID: 22710103
- Ma L, Hu BY, Liu Y, Vermilyea SC, Liu H, Gao L, Sun Y, Zhang X ,and Zhang SC (2012) Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice. Cell Stem Cell 10:455-464. PMCID: 3322292.
- Weick JP, Liu Y, and Zhang SC (2011: Human embryonic stem cell-derived neurons participate in and modulate neural network activity. Proc. Natl. Acad. Sci. USA, 108:29108-29194.
- Krencik R, Weick JH, Liu Y, Zhang, Z, and Zhang SC (2011) Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nature Biotechnology, 29:528-534. PMCID 3111840
- Zhang X, Huang C, Pankratz MT, Chen J, Xi J, Li J, Yang Y, LaVaute TM, Li XJ, Ayala M, Bondarenko GI, Du ZW, Jin Y, Golos TG, and Zhang SC (2010) Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell, 7:90-100. PMCID: PMC2904346
- Pellett S, Du ZW, Pier CL, Tepp WH, Zhang SC, and Johnson EA (2011). Sensitive and quantitative detection of botulinum neurotoxin in neurons derived from mouse embryonic stem cells. Biochem Biophys Res Commun. 404:388-392. PMID: 21130748