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).
1. What signals regulate astrocyte maturation?
We previous found that astrocytes undergo sudden maturation in the first six month to one year of life in humans (Neuron 2016). The time course of astrocyte maturation precisely correlates with temporal changes of synapse density. What signals determine the timing of astrocyte maturation? Are there an intrinsic clock and/or an extrinsic trigger for astrocyte maturation? What mechanism synchronizes the maturation of astrocytes and neural circuits? Could defect in astrocyte development lead to neurodevelopmental disorders, e.g. autism?
2. How is astrocyte differentiation regulated?
Astrocytes are the most abundant type of glia cell in the brain. They are critical for synapse formation and elimination. Compared to understanding of the differentiation of neurons and oligodendrocytes, our knowledge of astrocyte differentiation is very limited. We are currently investigating this fundamental question in developmental neurobiology.
3. Can we improve treatment of glioblastoma by studying astrocyte development?
Glioblastoma is the most common type of malignant primary brain tumor in adults. Current median survival for glioblastoma patients is only 15 months. Since glioblastoma cells and astrocyte progenitors have similar cellular and molecular properties, can we gain insight into treating glioblastoma by studying the development of astrocyte progenitors?