- Professor, Departments of Neuroscience and Neurology
- (608) 265-2543
M.D. Wenzhou Medical College, Ph.D. University of Saskatchewan
Human stem cells & neural regeneration
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, Alexander disease and Alzheimer’s disease.Using the state-of-the-art genome 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 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, motor neuron diseases and spinal cord injury, respectively. To ensure safe and appropriate functional recovery, we have further built stem cells with functional switches.
- 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.
- 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.
- 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.