Summary of previous research
1. Are human astrocytes different from mouse astrocytes?
Astrocytes are involved in almost every type of neurological and psychiatric disorder, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, autism, stroke, and traumatic central nervous system injury. For example, astrocytes expressing mutant form of proteins involved in ALS accelerate motor neuron death. Most of our knowledge of astrocyte biology is based on rodent model studies. Are human astrocytes different from mouse astrocytes? Can we fully understand the role of astrocytes in human neurological and psychiatric disorders based on mouse model studies? A major obstacle in studying human astrocytes is that it has been difficult to purify and culture them. We developed the first method to acutely purify developing and adult human astrocytes. We found that human astrocytes have similar abilities to murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. We next performed RNA-sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci, and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells. With these profiles, we identified novel human-specific astrocyte genes, and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes (Neuron 2016).
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 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 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 regulates astrocyte maturation?
Immature and mature astrocytes differ in their abilities to support neuronal growth and their responses to injuries. What signals controls 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).
1. How are human and mouse astrocytes different?
Astrocytes are involved in almost every type of neurological disorder of the central nervous system. However, our knowledge of astrocyte biology is mostly based on mouse studies. Most drug candidates identified in mouse models fail in human clinical trials for neurological disorders. There are a variety of reasons behind clinical trial failures. One of them is the potential biological difference between human and mouse cells. We are trying to identify differences between human and mouse astrocytes and use the knowledge to inform translational research for neurological disorders.
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 remain 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 glia and vascular 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 and vascular 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.