Neurological disorders, such as stroke and brain tumors, affect up to one billion people worldwide. Finding new treatments and understanding how these neurological disorders develop requires a better understanding of the complex interactions that occur in the brain. Our lab’s primary interest is studying interactions between brain vasculature (blood vessels) and the nervous system (glial cells and neurons). By combining electrophysiology and in vivo imaging with genetic methods, we hope to determine how the brain builds the gliovascular and neurovascular network during development and how this network can be damaged as a result of a stroke and then repaired.
Current treatment methods for patients with gliomas are hampered by a poor understanding of underlying biology. Glial cells are critical for brain metabolism, neuronal protection, and cell-cell communication. As a group with long-term experience in studying the function and development of astrocytes and NG2 glia, we are interested in how gliomas interact with adjacent normal glial cells and how glial cells create a microenvironment that influences glioma cell survival, proliferation, and invasion.
Neuron/Glia- Blood Vasculature Interactions
Development of New Tools
Although pericytes are located along vessels in both the central nervous system and other organs, astrocytic endfeet cover only the vasculature in the central nervous system. It remains unclear whether there are subtypes of pericytes in blood vessels and, if so, what their functions are in the brain. There is also little information available about how different subtypes of pericytes interact with glial cells or neurons in the brain.
To answer these questions, we will introduce techniques including electrophysiology and in vivo imaging into the study of brain pericytes. The goal is to isolate pericytes from several sources (arterioles, precapillaries, capillaries, postcapillaries and venules) to characterize the molecular and cellular profile of pericytes from these different locations. We have already established an electrophysiological technique to record individual pericytes within different segments of blood vessels in acutely isolated brain slices.
Formation of Gliovascular Interface
Glial cells constitute approximately half of the cells in the human brain. As the largest population of glial cells, astrocytes are crucial for the survival and function of neurons. Together with brain vasculature, astrocytic endfeet form an intricate structure called the gliovascular interface. This interface is critical for the transport of glucose from the blood to neurons, the regulation of cerebral blood flow and the maintenance of the blood-brain barrier. Detachment of astrocytic endfeet from the vascular membrane is responsible for brain edema and results in neurodegeneration. Restoring this function after stroke is critical to improving functional brain recovery in patients.
How the gliovascular interface forms and develops is unclear. We are studying the cellular and molecular mechanisms for interactions between brain vasculature and astrocytes with genetic manipulation and time-lapse slice or in vivo imaging.
The brain consists of multiple cell types that form a complex neuron-glia-blood vasculature network. During glioma (brain tumor) development, tumor cells infiltrate normal brain tissue and interact with adjacent stromal cells in this network . The network provides glioma cells with an appropriate environment for colonization, growth and infiltration. However, the role of normal glial cells, which constitute 50 percent of cells in the human brain and are critical for a number of functions (brain metabolism, neuronal protection and cell-cell communication), in glioma progression is poorly understood. Improving our understanding of glia-glioma interactions and discovering the underlying mechanisms are critical for the diagnosis, prognosis and treatment of pediatric glioma and necessary to identify new therapeutic targets.
We are currently investigating if and how different types of glial cells, especially astrocytes, create a microenvironment that promotes glioma cell survival, proliferation and invasion. This includes characterization of the fate and potential functional alterations of astrocytes adjacent to gliomas in vivo. We will perform longitudinal time-lapse imaging to characterize astrocyte properties (survival, proliferation and progeny) within and close to gliomas at different developmental stages. This will provide researchers with a functional paradigm for glioma growth from its initiation through the late stage.
Development of New Tools
We are interested in establishing new tools and methods to study how gliovascular units behave during strokes and in brain tumor in vivo.
Currently, it is difficult for researchers to take advantage of advanced live-imaging technologies in stroke studies, particularly in the developing mouse brain, due to vascular surgical challenges. We have developed a novel approach to induce focal ischemia with precise control of infarct size and occlusion duration in mice at any postnatal age (Jie et al., Nature Methods, 2016). We achieved the occlusion, which is reversible, via micromagnet-mediated aggregation of magnetic nanoparticles within a blood vessel (see below). In combination with longitudinal live imaging, we will investigate underlying mechanisms of disruption and repair of neurovascular units in vivo under ischemic stroke.
About Dr. Ge
Woo-Ping Ge obtained his B.S. in biochemistry (2000) at East China Normal University and his Ph.D. in neurobiology (2005) at the Institute of Neuroscience, Chinese Academy of Sciences. His doctoral research focused on neuron-glia signaling. Dr. Ge conducted his postdoctoral research on glial cell generation at the University of California, San Francisco.
Dr. Ge joined the faculty as an assistant professor at Children’s Research Institute (CRI) at the UT Southwestern Medical Center in September 2013.
Jia, J.M., Chowdary, P.D., Gao, X., Ci, B., Li, W., Mulgaonkar, A., Plautz, E.J., Hassan, G., Kumar, A., Stowe, A.M., Yang, S.H., Zhou, W., Sun, X., Cui, B*., and Ge, W.P*. (2017) Control of cerebral ischemia with magnetic nanoparticles. Nat Methods. 14, 160-166. (PubMed)
Peng, C., Gao, X., Xu, J., Du, B., Ning, X., Tang, S., Bachoo, R.M., Yu, M., Ge, W.P.*., and Zheng, J.*. (2012) Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles. Nano Res. 10, 1366–1376. *co-corespondent author
Ge, W.P., Miyawaki, A., Gage, F.H., Jan, Y.N., and Jan, L.Y. (2012) Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484, 376—380. (PubMed)
Ge, W.P., Zhou, W., Luo, Q., Jan, L.Y., and Jan, Y.N. (2009). Dividing glial cells maintain differentiated properties including complex morphology and functional synapses. Proc Natl Acad Sci U S A 106, 328—333. (PubMed)
Ge, W.P.*, Yang, X.J.*, Zhang, Z., Wang, H.K., Shen, W., Deng, Q.D., and Duan, S. (2006). Long-term potentiation of neuron-glia synapses mediated by Ca2+-permeable AMPA receptors. Science 312, 1533—1537. (PubMed) *co-first author