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: 
Discovery of Novel Cell Surface Markers for Purification of Embryonic Dopamine progenitors for Transplantation in Parkinson's Disease Animal Models.Fathi A, Mirzaei M, Dolatyar B, Sharifitabar M, Bayat M, Shahbazi E, Lee J, JavanM, Zhang SC, Gupta V, Lee B, Haynes PA, Baharvand H, Salekdeh GH.Mol Cell Proteomics. 2018 May 29. pii: mcp.RA118.000809. doi: 10.1074/mcp.RA118.000809. [Epub ahead of print]PMID: 29848781
Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease.Wang L, Xia J, Li J, Hagemann TL, Jones JR, Fraenkel E, Weitz DA,Zhang SC, Messing A, Feany MB.Nat Commun. 2018 May 15;9(1):1899. doi: 10.1038/s41467-018-04269-7.PMID: 29765022
Modeling Down Syndrome with Patient iPSCs Reveals Cellular and MigrationDeficits of GABAergic Neurons.Huo HQ, Qu ZY, Yuan F, Ma L, Yao L, Xu M, Hu Y, Ji J, Bhattacharyya A, Zhang SC, Liu Y.Stem Cell Reports. 2018 Apr 10;10(4):1251-1266. doi: 10.1016/j.stemcr.2018.02.001. Epub 2018 Mar 8.PMID: 29526735
A multi-dimensional characterization of anxiety in monozygotic twin pairs reveals susceptibility lociin humans.Alisch RS, Van Hulle C, Chopra P, Bhattacharyya A, Zhang SC, Davidson RJ, Kalin NH, Goldsmith HH.Transl Psychiatry. 2017 Dec 11;7(12):1282. doi: 10.1038/s41398-017-0047-9.PMID: 29225348
PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease.Oksanen M, Petersen AJ, Naumenko N, Puttonen K, Lehtonen Š, Gubert Olivé M, Shakirzyanova A, Leskelä S, Sarajärvi T, Viitanen M, Rinne JO, Hiltunen M, Haapasalo A, Giniatullin R, Tavi P, Zhang SC, Kanninen KM, Hämäläinen RH, Koistinaho J.Stem Cell Reports. 2017 Dec 12;9(6):1885-1897. doi: 10.1016/j.stemcr.2017.10.016. Epub 2017 Nov 16.PMID: 29153989
A neuroprotective astrocyte state is induced by neuronal signalEphB1 but fails in ALS models.Tyzack GE, Hall CE, Sibley CR, Cymes T, Forostyak S, Carlino G, Meyer IF, Schiavo G, Zhang SC, Gibbons GM, Newcombe J, Patani R, Lakatos A.Nat Commun. 2017 Oct 27;8(1):1164. doi: 10.1038/s41467-017-01283-z.PMID: 29079839
Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons from Adult Common Marmoset Fibroblasts.Vermilyea SC, Guthrie S, Meyer M, Smuga-Otto K, Braun K, Howden S, Thomson JA,Zhang SC, Emborg ME, Golos TG.Stem Cells Dev. 2017 Sep 1;26(17):1225-1235. doi: 10.1089/scd.2017.0069. Epub 2017 Jul 24.PMID: 28635509
Sporadic ALS Astrocytes InduceNeuronal Degeneration In Vivo.Qian K, Huang H, Peterson A, Hu B, MaragakisNJ, Ming GL, Chen H, Zhang SC.Stem Cell Reports. 2017 Apr 11;8(4):843-855. doi: 10.1016/j.stemcr.2017.03.003. Epub 2017 Mar 30.PMID: 28366455
Neural Subtype Specification from Human Pluripotent Stem Cells.Tao Y, Zhang SC.Cell Stem Cell. 2016 Nov 3;19(5):573-586. doi: 10.1016/j.stem.2016.10.015. Review.PMID: 27814479
Real-Time Intraoperative MRI Intracerebral Delivery of Induced Pluripotent Stem Cell-Derived Neurons.Vermilyea SC, Lu J, Olsen M, Guthrie S, Tao Y, Fekete EM, Riedel MK, Brunner K, Boettcher C, Bondarenko V, Brodsky E, Block WF, Alexander A, Zhang SC, Emborg ME.Cell Transplant. 2017 Apr 13;26(4):613-624. doi: 10.3727/096368916X692979. Epub 2016 Sep 14.PMID: 27633706