Su-Chun Zhang, MD, PhD

T613 Waisman Center
1500 Highland Avenue
Madison, WI 53705
(608) 265-2543
Focus Groups: 
MD, Wenzhou Medical College
PhD, Cell Biology, University of Saskatchewan
MSc, Neurobiology, Shanghai Medical University
Research Summary: 
Stem Cell Approaches to Neural Degeneration and Regeneration
Research Detail: 

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.

Selected Publications: 
Chen H*, Qian K*, Du Z*, Cao J, Petersen AJ, Liu H, Blackbourn LW IV, Huang C, Errigo A, Yin Y, Lu J, Ayala M, Zhang SC (2014): Modeling ALS with iPSCs Reveals that Mutant SOD1 Misregulates Neurofilament Balance in Motor Neurons. Cell Stem Cell, online.
Qian K, Huang C, Chen H, Blackbourn LW IV, Chen Y, Cao J, Yao L, Du Z, Zhang SC (2014): A simple and efficient system for regulating gene expression in human pluripotent stem cells and derivatives. Stem Cells, 32(5): 1230-8.
Liu Y, Weick JP, Krencik R, Liu H, Zhang X, Ma L, Zhang SC (2013): Medial ganglionic eminence-like cells from human embryonic stem cells correct learning and memory deficits. Nature Biotechnol, 31: 440-447. NINMSID#471832
Weick JP, Held DL, Bonadurer G, Doers ME, Liu Y, Clark A, Maguire C, Knackert JA, Molinarolo K, Musser M, Yao L, Yin Y, Lu J, Zhang X, Zhang SC, Bhattacharyya A (2013): Deficits in human trisomy 21 iPSCs and neurons: A model for Down syndrome intellectual disability. Proc. Natl. Acad. Sci. USA, 110:9962-67.
Lu J, Liu H, Huang C, Chen H, Du Z, Liu Y, Sherafat MA, Zhang SC (2013): Generation of integration-free and region-specific neural progenitors from primate fibroblasts. Cell Reports, 3: 1580-1591. PMC 3786191.
Emborg ME#, Liu Y#, Xi J, Zhang X, Yin Y, Joers V, Swanson C, Holden JE, Zhang SC (2013): Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain. Cell Reports, 3: 646-650. NIHMSID #448010
Du ZW, Ma L, Phillips C, Zhang SC (2013): miR-200 and miR96 families regulate neural induction from human embryonic stem cells. Development,140:2611-2618. PMC3666386.
Ma L, Hu BY, Liu Y, Vermilyea SC, Liu H, Gao L, Sun Y, Zhang X , 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.
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. PMCID 3111840.
Weick JP, Liu Y, Zhang SC (2011): Human embryonic stem cell-derived neurons participate in and modulate neural network activity. Proc. Natl. Acad. Sci. USA, 108:20189-194 (open access).
Jones JR, Zhang SC (2016): Engineering Human Cells and Tissues Through Pluripotent Stem Cells. Current Opinion in Biotechnology, 40:133-138. NIHMS774511.
Sances S, Bruijn L, Chandran S, Eggan K, Ho R, Klim J, Livesey MR, Lowry E, Rushton R, Sareen D, Wichterle H, Zhang SC, Svendsen CN (2016): Modeling ALS using motor neurons from induced pluripotent stem cells: Challenges and future directions. Nature Neuroscience, 16:542-53.
Chen Y, Xiong M, Dong Y, Haberman A, Cao J, Liu H, Zhang SC (2016): Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease. Cell Stem Cell, 18: 817-26, NIHMSID 784547.
Kadoya K, Lu P, Nguyen K, Lee-Kubli C, Yao L, Poplawski G, Dulin J, Takashima Y, Biane J, Conner J, Zhang SC, Tuszynski MH (2016): Robust Corticospinal Regeneration Enabled by Spinal Cord Reconstitution with Homologous Neural Grafts. Nature Medicine, 22: 479-87. NIHMS760169.
Lu J, Zhong X, Liu H, Hao L, Huang CT, Sherafat MA, Jones J, Ayala M, Li L, Zhang SC (2016): Generation of Functional Human Serotonin Neurons. Nature Biotechnology, 34:89-94. PMCID4711820.
Liu H, Lu J, H Chen, Z Du, Li XJ, Zhang SC (2015): Motor Neurons from Spinal Muscular Atrophy Patients Exhibit Hyper-excitability. Scientific Reports, 5:12189. PMCID 4507262.
Chen Y, Cao J, Xiong M, Petersen A, Dong Y, Tao Y, Huang C, Du Z, Zhang SC (2015): Engineering Human Stem Cell Lines with Inducible Gene Knockout using CRISPR/Cas9. Cell Stem Cell, 17: 233-44 PMCID 4530040.
Du Z, Chen H, Liu H, Zhang SC (2015): Generation and Expansion of Pure Motor Neuron Precursors from Human Stem Cells. Nature Communication, 6:6626. PMC4375778.
Chen H, Qian K, Chen W, Hu B, Ma L, Du Z, Liu H, Knoble K, Zhang SC (2015): Human-derived neural progenitors replace astrocytes in adult mice. Journal of Clinical Investigation, 125: 1033-42. PMC 4362241.
Chen H, Qian K, Du Z, Cao J, Petersen AJ, Liu H, Blackbourn LW IV, Huang C, Errigo A, Yin Y, Lu J, Ayala M, Zhang SC (2014): Modeling ALS with iPSCs Reveals that Mutant SOD1 Misregulates Neurofilament Balance in Motor Neurons. Cell Stem Cell, 14: 796-809. PMCID4230530.