Dr. Su-Chun Zhang’s laboratory aims to answer 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 embryonic stem cells (ESCs) that recapitulate key events occurring during 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 ESC 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.
Our laboratory focuses on addressing how functionally diversified neuronal and glial subtypes are born in the building and rebuilding 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). By following the developmental principles, we have successfully directed hPSCs to regionally and functionally specialized neural cells, including cortical glutamatergic neurons and GABA interneurons, striatal medium spiny GABAergic neurons, basal forebrain cholinergic neurons, midbrain dopamine neurons, spinal motoneurons, oligodendrocytes, and region-specific astrocyte subtypes. 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, maintain, 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 or blood cells of patients with neurological disorders, focusing on motor neuron diseases (ALS, SMA), Down syndrome and Alzheimer’s disease. Using the state-of-the-art gene editing technology (TALENs, CRISPR) we have built transgenic disease human cell lines and corrected mutations in patient iPSCs. We are now dissecting cellular and molecular processes that underlie neural degeneration. We are also 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 type of 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. To ensure safe and appropriate functional recovery, we have further built stem cells with functional switches. With the understanding of the regulatory process of human neural specification and reprogramming, our long-term goal is to rebuild our aging or diseased brain from within.
Lu J, Zhong X, Liu H, Hao L, Huang CT, Sherafat MA, Jones J, Ayala M, Li L, Zhang SC. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nature Biotechnology. 34(1):89-94. doi: 10.1038/nbt.3435.
Zhong X, Hao L, Lu J, Ye H, Zhang SC, Li L. (2016) Quantitative analysis of serotonin secreted by human embryonic stem cells-derived serotonergic neurons via pH-mediated online stacking-CE-ESI-MRM. Electrophoresis. 37(7-8):1027-30. doi: 10.1002/elps.201500496.
Hoeber J, Trolle C, Konig N, Du Z, Gallo A, Hermans E, Aldskogius H, Shortland P, Zhang SC, Deumens R, Kozlova EN. (2015) Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury. Scientific Reports. 8;5:10666. doi: 10.1038/srep10666.
Chen Y, Cao J, Xiong M, Petersen AJ, Dong Y, Tao Y, Huang CT, Du Z, Zhang SC. (2015) Engineering Human Stem Cell Lines with Inducible Gene Knockout using CRISPR/Cas9. Cell Stem Cell. 6;17(2):233-44. doi: 10.1016/j.stem.2015.06.001.
Li M, Pehar M, Liu Y, Bhattacharyya A, Zhang SC, O'Riordan KJ, Burger C, D'Adamio L, Puglielli L. (2015) The amyloid precursor protein (APP) intracellular domain regulates translation of p44, a short isoform of p53, through an IRES-dependent mechanism. Neurobiology of Aging. 36(10):2725-36. doi: 10.1016/j.neurobiolaging.
Chen Y, Xiong M, Zhang SC. (2015) Illuminating Parkinson's therapy with optogenetics. Nature Biotechnology. 33(2):149-50. doi: 10.1038/nbt.3140.
Du ZW, Chen H, Liu H, Lu J, Qian K, Huang CL, Zhong X, Fan F, Zhang SC. (2015) Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nature Communications. 25;6:6626. doi: 10.1038/ncomms7626.
Liu H, Lu J, Chen H, Du Z, Li XJ, Zhang SC. (2015) Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability. Science Reports. 20;5:12189. doi: 10.1038/srep12189.
Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q, Ananiev GE, Mok JC, Lin BR, Lu J, Chiao C, Cherney R, Li H, Zhang SC, Chang Q. (2014) Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Human Molecular Genetics. 23(11):2968-80.
Qian K, Huang CL, Chen H, Blackbourn LW 4th, Chen Y, Cao J, Yao L, Sauvey C, 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.
Lu J, Bradley RA, Zhang SC. (2014) Turning reactive glia into functional neurons in the brain. Cell Stem Cell. 14(2):133-4.
Chen H, Qian K, Du Z, Cao J, Petersen A, Liu H, Blackbourn LW 4th, Huang CL, 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(6):796-809.
Doers ME, Musser MT, Nichol R, Berndt ER, Baker M, Gomez TM, Zhang SC, Abbeduto L, Bhattacharyya A. (2014) iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth. Stem Cells and Development. 1;23(15):1777-87.