A Next Generation Human Induced Pluripotent Stem Cell-derived CNS Model for the Study of Tauopathy
Wednesday, June 8, 2022
10:00 AM-12:00 PM
BIOMED Master's Thesis Defense
Title:
Development of a Next Generation Human Induced Pluripotent Stem Cell-derived CNS Model for the Study of Tauopathy
Speaker:
Simeon Kofman, Master’s Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Advisors:
Liang Oscar Qiang, MD, PhD
Assistant Professor
Department of Neurobiology and Anatomy
Drexel University College of Medicine
Fred Allen, PhD
Teaching Professor
Associate Dean for Undergraduate Education
School of Biomedical Engineering, Science and Health Systems
Drexel University
Abstract:
The emergence of human induced pluripotent stem cell (hiPSC) technology has led to the development of several useful 3D in vitro modelling platforms for the study of tauopathy. However, most of these models fail to capture the full range of implicated central nervous system (CNS) cell types, including endothelial cells and microglia, thus limiting their utility in the study of certain aspects of the disease. The first goal of this study was to design and develop a 3D human in vitro assembloid model that incorporates populations of endothelial cells and microglia. This was done by combining organoid-dissociated neuroectodermal cells, human umbilical vein endothelial cells (HUVEC), and hiPSC-derived microglia in an AggreWell system. Markers specific to neural progenitor cells (NPC), neurons, astrocytes, endothelial cells, and microglia were observed within these models, as was the emergence of physiologically relevant sub-structures such as the neuroepithelium and the blood-brain-barrier.
The second goal of this study was to use this model to explore cellular and molecular deficits introduced by hiPSCs carrying the tau P301S mutation. Given that both astrocytes and microglia have been implicated in several aspects of tauopathy, including increased neuroinflammation and the spread of phosphorylated tau, we decided to look at morphological changes within these cell types as well as their interaction with phosphorylated tau species. Through immunohistochemical labelling analyses, mutation assembloids were found to have increased levels of total tau, more rod-like microglia, and appear to show integration of phosphorylated tau into both astrocytes and microglia. Ultimately, these results suggest utility in using this assembloid model for studying tauopathy. In addition to optimizing assembloid models to include larger populations of endothelial cells and microglia, future work should aim to explore the cellular and molecular findings across various time points of modelling, to understand how they change with the progression of the disease.
Contact Information
Natalia Broz
njb33@drexel.edu