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 the self-renewal of neural progenitors. Information learned from these studies sets up the foundation for us to switch, maintain, or re-program neural cell types. These cell types also form the building blocks for printing neural tissues by design, enabling us to decode the intricate circuits in our human brain.
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), Alexander disease, Down syndrome, and Alzheimer’s disease. Using the state-of-the-art genome editing technology (CRISPR) we have built transgenic disease human cell lines and corrected mutations in patient iPSCs. We are now engineering cells to manifest disease-relevant phenotypes that normally occur decades in life so that the cellular and molecular underpinning of neural degeneration may be dissected. We are also transforming these cellular models to templates for drug discovery.
We have 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. 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.
1. Tao Y and Zhang SC (2016): Neural subtype specification from human pluripotent stem cells. Cell Stem Cell, 19: 573-586. PMCID5127287.
2. 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, PMCID 4892985.
3. 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. PMCID4860037.
4. 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. PMCID 5015775.
5. 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.
6. 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.
7. Du ZW, Chen H, Liu H, Lu J, Qian K, Huang CL, Zhong X, Fan F, Zhang SC (2015): Generation and Expansion of Pure Motor Neuron Precursors from Human Stem Cells. Nature Communication, 6:6626. PMC4375778.
8. 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.
9. Liu Y, Weick JP, Krencik R, Liu H, Zhang X, Ma L, Zhang SC (2013): Human embryonic stem cell-derived basal forebrain cholinergic neurons reverse learning and memory deficits. Nature Biotechnology, 31: 440-447. PMC 3711863.
10. 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.