PROGRAMMNG AND REPROGRAMMING OF NEURAL STEM CELLS
Our laboratory focuses on addressing how functionally diversified neuronal and glial subtypes are born in the building and rebuilding of our human brain. Over the past decade, 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, striatal medium spiny GABAergic neurons, basal forebrain cholinergic neurons, midbrain dopamine neurons, spinal motoneurons, oligodendrocytes, and region-specific astrocyte subtypes. We have also discovered regulatory mechanisms that are quite unique to human neural development, including the identification of Pax6 as a transcriptional determinant of the neuroectoderm. 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 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 of patients with neurological disorders, focusing on motor neuron diseases (ALS, SMA), Huntington’s disease, Down syndrome and Alzheimer’s disease. We are now dissecting cellular and molecular processes that underlie the neural degeneration. We have also established the state-of-the-art gene editing technology to build reporter and transgenic disease human cell lines. We are 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, and motor neuron diseases, respectively. With the understanding of the regulatory process of human neural programming and reprogramming, our long-term goal is to rebuild our aging or diseased brain from within.
- 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, online.
- Liu H, Lu J, Li XJ, Zhang SC (2015): Motor Neurons from Spinal Muscular Atrophy Patients Exhibit Hyper-excitability. Scientific Reports, online.
- 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. PMC4362241.
- 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. PMCID 4230530.