Summary of previous research

1.     Are human astrocytes different from mouse astrocytes?

Human-mouse differences are a major barrier in translational research. Mouse models of neurological disorders often incompletely recapitulate phenotypes seen in human patients, but the underlying cellular and molecular differences are largely unknown. Astrocytes play important roles in neurological disorders such as stroke, injury, and neurodegeneration. However, the similarities and differences between human and mouse astrocytes are unclear. Combining analyses of acutely purified astrocytes, experiments using serum-free cultures of primary astrocytes, and xenografted chimeric mice, we found extensive conservation in astrocytic gene expression between humans and mice. However, genes involved in defense response and metabolism showed species differences. These differences were intrinsically programmed in astrocytes rather than induced by signals from neurons and other cells in the brain environment. Human astrocytes exhibited greater susceptibility to oxidative stress than mouse astrocytes, due to differences in mitochondria physiology and detoxification pathways, potentially contributing to milder phenotype in mouse models of neurodegeneration compared to human patients. Mouse astrocytes, but not human astrocytes, activate a molecular program for neural repair under hypoxia, potentially underlying greater recovery in mouse models of ischemic stroke compared to human patients. Furthermore, human astrocytes, but not mouse astrocytes, activate the antigen presentation pathway under inflammatory conditions. These findings provide a mechanistic understanding of the differences between human and mouse models of neurological disorders and uncover new approaches to improve the models. (Neuron 2016) (Nature Communications 2021) (Journal of Neuroscience, in press)

2.     What are the gene expression differences between neuron, glia, and vascular cells?

The major cell classes of the brain differ in their developmental processes, metabolism, signaling, and function. To better understand the functions and interactions of the cell types that comprise these classes, we acutely purified representative populations of neurons, astrocytes, oligodendrocyte precursor cells, newly formed oligodendrocytes, myelinating oligodendrocytes, microglia, endothelial cells, and pericytes from the mouse cerebral cortex. We generated a transcriptome database for these 8 cell types by RNA sequencing and used a sensitive algorithm to detect alternative splicing events in each cell type. Bioinformatic analyses identified thousands of new cell type-enriched genes and splicing isoforms that will provide novel markers for cell identification, tools for genetic manipulation, and insights into the biology of the brain. For example, our data provides clues as to how neurons and astrocytes differ in their ability to dynamically regulate glycolytic flux and lactate generation due to the unique splicing of the glycolytic enzyme PKM2. This dataset will provide a powerful new resource for understanding the development and function of the brain (J Neurosci 2014).

3.     What signals regulate astrocyte maturation?

Immature and mature astrocytes differ in their abilities to support neuronal growth and their responses to injuries. What signals control the maturation of astrocytes as an organism matures? We found that astrocyte-to-astrocyte contact as well as astrocytic interactions with other cell types in the brain regulates astrocyte maturation (Glia 2019).  

Current projects

1.     How do glial cells talk to each other?

Astrocytes, microglia, oligodendrocytes, and vascular cells communicate with neurons and the interactions are critical for the function of the central nervous system. How glia cells communicate with each other remains not fully understood. We combine genetic and cell culture methods to characterize interactions between different cell types and identify the function of glia-glia and glia-vascular interactions in brain development, function, and disease.

2.     How do human astrocytes change in neurological diseases?

Mouse astrocytes respond to injury and diseases by cellular, molecular, and physiological changes called reactive astrogliosis, a process beneficial in some conditions and detrimental in others. How human astrocytes change in neurological diseases remains unclear. We use cell purification and transcriptome profiling to characterize changes of human astrocytes in diseases such as epilepsy, brain tumors, and neurodegeneration.

3.     How do embryonic neural stem cells transform into adult neural stem cells?

Neural stem cells hold great promise for replacing neurons and glia damaged in neurological disorders. However, a step in neural stem cell development remains poorly understood: the transition from the embryonic to adult neural stem cells. We use mouse genetics and genomics to investigate this transition.