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As a central tenet of regenerative biology is that processes controlling tissue generation during development often control its regeneration, the basic and translational stem cell research we are pursuing critically bridges between the understanding of human neural development in heath and disease, and the development of stem cell regenerative medicine.

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Astrocytes, also called astroglia, are a major cellular constituent of the central nervous system (CNS) and play crucial roles in brain development, function, and integrity. Increasing evidence demonstrates that astroglia dysfunction occurs in a variety of neurological disorders ranging from CNS injuries to genetic diseases and chronic degenerative conditions. These new insights herald the concept that transplantation of astroglia could be of therapeutic value in treating the injured or diseased CNS. Recent technological advances in the generation of human astroglia from stem and progenitor cells have been prominent. Currently, we also focus on studying human astroglia development, developmental interactions between human astroglia and oligodendroglia, and establishing human PSC-derived astroglia therapies for treating myelin loss disorders, such as brain hypoxic-ischemic injury and multiple sclerosis, through promoting proliferation and maturation of resident oligodendroglia progenitor cells and further enhancing myelination or remyelination (Figure 2).

Down syndrome (DS) is the most common genetic cause of intellectual disability and developmental delay, and it affects one in every 700-800 live births. Also called Trisomy 21, this condition occurs when an individual has 3 copies of human chromosome 21 (HSA21). Currently, there are no approved treatments to improve cognitive function in patients with DS. One of the major hurdles in developing treatments is the lack of knowledge on the precise mechanism underlying the cognitive impairments. Our current knowledge on the neuropathophysiology of DS is mainly gained from studies in transgenic mouse models and human DS fetal brain tissues. However, these strategies have limited utility because human tissues are relatively inaccessible and the mouse models only demonstrate an incomplete trisomy of HSA21.

The advent of induced pluripotent stem cell (iPSC) technology has provided a new approach to the establishment of human cellular models for studying the pathogenesis of neurodevelopmental and neurodegenerative diseases. We have generated human iPSCs directly from DS patients and differentiated them to patients’ own brain cells. Moreover, we have established 2-dimensional (2D) stem cell neural differentiation model, 3D cerebral organoid model as well as in vivo humanized chimeric mouse brain model to study the disease mechanisms (Figure 1).

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Imbalance of excitatory and inhibitory neurotransmission is one of the major causes underlying the cognitive deficit in many neurological disorders, including DS. Currently, we focus on studying how DS astroglia regulate the formation of functional excitatory synapses, how the normal development of inhibitory GABAergic neurons is changed by expression of the genes triplicated in HSA21, and how these cellular and molecular abnormalities collectively contribute to abnormal synaptic plasticity and cognitive deficit of DS. We also expect to establish these stem cell studies as a template for the investigation of other neurological diseases, such as autism and schizophrenia.    

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The goal of our research is to create human pluripotent stem cell (PSC) neural differentiation models for studying human neural development pathways and corresponding pathogenesis of neurodevelopmental diseases, and for developing stem cell regenerative medicine to treat neurological disorders. We have been using a combination of multidisciplinary techniques in our research, stem cell reprogramming, electrophysiology/patch-clamp recording, imaging techniques, molecular/cell biology (including CRISPR/cas9 technology), biochemistry, pharmacology, microarray and RNA-sequencing techniques, transgenic and surgically induced animal models, and animal behavioral testing.

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