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Development of a Human Neurovascular Unit Organotypic Systems Model of Early Brain Development
Citation:
Schwab, A. AND S. Hunter. Development of a Human Neurovascular Unit Organotypic Systems Model of Early Brain Development. U.S EPA: 3rd Annual STAR Organotypic Culture Models (OCM) Progress Review Meeting, rtp, Nc, May 22 - 23, 2018.
Impact/Purpose:
The focus of this poster presentation will be on the development of a human experimental model system for studying the impact of chemical-induced thyroid hormone disruption on neural morphogenesis. Thyroid hormone disruption is a major concern for children's health as there are many morphological effects produced by disruption of the thyroid hormone axis during human brain development. This project focuses on neurovascular unit (NVU) morphogenesis as a target of thyroid hormone disruption. A 2-compartment microfluidic bioreactor and a transwell system will be stablished to evaluate the consequences of altered thyroid hormone availability during critical neurodevelopmental periods. This cutting edge human system will be a valuable tool to bio-mimic the human NVU and allow the establishment of a quantitative relationship between altered thyroid hormone levels and neuromorphogenesis. Ultimately, this system will be essential in translating chemical effects on thyroid hormone availability and neural morphogenesis.
Description:
The inability to model human brain and blood-brain barrier development in vitro poses a major challenge in studies of how chemicals impact early neurogenic periods. During human development, disruption of thyroid hormone (TH) signaling is related to adverse morphological effects including altered brain development and function; however, the quantitative relationship between mild and moderate levels of TH disruption on neural morphogenesis, particularly in the face of xenobiotic challenge, remains unknown. We focus on the human neurovascular unit (NVU) and early nervous system development using a dynamic (ibidi 2-compartment microfluidic slide) and a static (transwell) model system comprised of endothelial, pericyte, and neural progenitor cells. We demonstrate low permeability across the NVU/blood-brain barrier as well as glio- and neuro-genesis of EZ Sphere stem cell-derived neural progenitors. Both dynamic and static model systems have been analyzed with automated high-content imaging allowing for robust, non-biased measurements of neural differentiation and neurite outgrowth which will be crucial for future toxicity testing. Importantly, we are also able to assess endothelial, pericyte and glia cell morphology for chemical induced perturbations. Future studies to evaluate the morphological effects of thyroid hormone disrupting chemicals will allow a determination of the consequences of hypothyroidism or TH signaling disruption during critical windows of early brain development. Combined, these novel, complementary human NVU model systems will be useful in understanding the consequences of chemical effects on early neurodevelopment periods which one day may contribute to understanding the mechanisms underlying neurobehavioral disorders. Ultimately, the information gained using these advanced model systems may have a profound effect on advancing children’s health. This abstract does not represent EPA policy.