Tré Mills Dissertation Defense (5/10/21): Gliovascular Plasticity in the Maintenance of Cerebrovascular Health
Dissertation Defense: Gliovascular Plasticity in the Maintenance of Cerebrovascular Health
Graduate Student, Virginia Tech Translational Biology, Medicine, and Health
Graduate Research Assistant, Sontheimer Lab, Fralin Biomedical Research Institute at VTC
May 10, 2021 at 3:00 p.m.
Zoom access information for this event will be distributed by the candidate.
About this Dissertation
Astrocytes comprise the most abundant cell population in human brain. First described by Virchow as being the "glue" of the brain, modern research has truly extended our knowledge and understanding regarding the vast array of roles these cells execute under normal physiological conditions. Examples include neurotransmitter reuptake at the synapse, the regulation of blood flow at capillaries to meet neuronal energy demand, and maintenance/repair of the blood-brain barrier (BBB), which is comprised, in part, of tight junction proteins such zonula-occludens-1 (ZO1) and Claudin-5. Underlying the execution of these processes is the morphological and spatial arrangement of astrocytes between neurons and endothelial cells comprising blood vessels, where comprehensively speaking, these cells form what is known as the gliovascular unit. Astrocytes extend large processes called endfeet that intimately associate with and enwrap up to 99% of the cerebrovascular surface. Disruptions to this association can occur in the form of retracted endfeet, and this has been characterized in several disease states such as major depressive disorder, ischemia, and normal biological aging. Disruption can also take the form of cellular/protein aggregate intercalation, which our lab previously characterized in a human-derived glioma model and vascular amyloidosis human Amyloid Precursor Protein J20 (hAPPJ20) animal model. In both models, focal astrocyte-vascular disruptions coincided with perturbations to astrocyte control of blood flow, with deficits in BBB integrity present in the glioma model as well.
These findings lead to the preliminary work in this dissertation where we aimed to extend BBB findings in the glioma model to the hAPPJ20 vascular amyloidosis model. Immunohistochemical analysis in two-year old hAPPJ20 animal arterioles revealed that indeed in locations of vascular amyloid buildup and endfoot separation, there was a significant reduction in a tight junction protein critical for BBB maintenance, ZO1. This reduction in ZO1 expression was accompanied by extravasation of 70kDa FITC and the ~1kDa Cadaverine, suggesting that BBB integrity was compromised. These findings led to the objective of this dissertation, which was to determine if focal ablation of an astrocyte is sufficient to disrupt BBB integrity. By utilizing the in vivo 2Phatal single-cell apoptosis induction method, Mills, working in the Sontheimer Lab, found that 1) focal loss of astrocyte-vascular coverage does not result in barrier deficits, but rather induces a plasticity response whereby surrounding astrocytes extend processes to reinnervate vascular vacancies no longer occupied by previously ablated astrocytes; 2) replacement astrocytes are capable of inducing vasocontractile responses in blood vessels, and that 3) aging significantly attenuates the kinetics of this process. Mills then tested the hypothesis that focal loss of astrocyte-vascular coverage leads to a gliovascular structural plasticity response, in part, through the phosphorylation of signal transducer and activator of transcription 3 (STAT3) by Janus Kinase 2 (JAK2). This dissertation found that 4), this was indeed the case, and finally, 5) Mills determined that gliovascular structural plasticity occurs after reperfusion post-focal photothrombotic stroke. Together, the work presented in this dissertation sheds light on a novel plasticity response whereby astrocytes maintain continual cerebrovascular coverage and therefore physiological control. Future studies should aim to determine if 1) astrocytes also replace the synaptic contacts with neighboring neurons once held by a previous astrocyte, and 2) what therapeutic opportunity gliovascular structural plasticity may present regarding BBB repair following stroke.
More About the Candidate and Project
Virginia Tech Translational Biology, Medicine, and Health, Ph.D Candidate
Virginia Tech, B.S., Biological Sciences
Graduate Research Assistant, Sontheimer Lab and Center for Glial Biology in Health, Disease, and Cancer
Harold Sontheimer, Ph.D., Adjunct Professor, Fralin Biomedical Research Institute at VTC
- Michelle Olsen, Ph.D., Associate Professor and Director of Graduate Studies, School of Neuroscience, College of Science, Virginia Tech
- Michael Fox, Ph.D., Professor, Fralin Biomedical Research Institute at VTC, and Director, School of Neuroscience, College of Science, Virginia Tech
- John Chappell, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC
Secretary, Neuroscience Postdoctoral Graduate Student Association, October 2019-July 2020
Mills III W, Jiang S, Martin J, Woo A, Bergstresser M, Kimbrough I, Sontheimer H. Astrocyte plasticity ensures continued coverage of cerebral blood vessels and integrity of the blood-brain barrier, with plasticity declining with normal aging. Submitted.
Okyre B, Mills III W, Kowalski E, Amanda H, Qian Y, Wang X, Matson J, Theus M. A novel suppressive role for endothelial cell-specific EphA4 in leptomeningeal collateral remodeling. J Clin Invest. 2020;130(2):1024–1035.https://doi.org/10.1172/JCI131493
Campbell S, Muñoz-Ballester C, Chaunsali L, Mills III W, Yang J, Sontheimer H, Robel S. Potassium and glutamate transport is impaired in scar-forming tumor-associated astrocytes. Neurochemistry International. 2020; 133. https://doi.org/10.1016/j.neuint.2019.104268
Jiang S, Patel DC, Jongwoon K, Yang S, Mills III W, Zhang Y, Feng Z, Wang A, Guo Y, Kimbrough I, Sontheimer H, Jia X. Spatially expandable fiber-based probes as a multifunctional deep brain interface. Nat Commun 11, 6115 (2020). https://doi.org/10.1038/s41457-020-19946- 9
Lebovitz Y, Kowalski EA, Wang X, Kelly C, Lee M, McDonald V, Ward R, Creasey M, Mills W, Basso EKG, Hazy A, Hrubec T, & Theus MH (2019). Lactobacillus rescues postnatal neurobehavioral and microglial dysfunction in a model of maternal microbiome dysbiosis. Brain, Behavior, and Immun. 81, 617-629. doi: 10.1016/j.bbi.2019.07.025
Monavarfeshani A, Stanton G, Van Name J, Su K, Mills III W, Swilling K, Kerr A. Huebschman N, Su J, Fox M. LRRTM1 underlies synaptic convergence in visual thalamus. eLife 2018 Feb 9;7:e33498. PMID: 229424692; PMCID: PMC582628
Jiang S, Kadlec K, Marcano AL, Song J, Mills III W, Kimbrough I, Sontheimer H, Jia X. Nano- optoelectrodes integrated with flexible multifunctional fiber probes by high-throughput scalable fabrication. Accepted ACS Applied Materials & Interfaces.