Progress towards Recapitulation of the Human Brain in iPSC-Derived Brain Organoids

Abstract

Progress towards Recapitulation of the Human Brain in iPSC-Derived Brain Organoids By Reese Popkin Thesis under the direction of Dr. Leon Bellan iPSC-derived brain organoids offer the potential to examine the in vivo functionality of the human brain in a more in-depth fashion than currently available methods. However, current models lack the complexity required to fully recapitulate human brain development and functionality. Herein, we describe two approaches to increase the complexity in current brain organoid systems. In the first approach, we establish a workflow capable of 3D imaging of human brain organoids utilizing the CUBIC tissue clearing system. This approach was applied to characterize brain organoids exposed to spatial gradients of ventral (SHH) and dorsal (BMP4) morphogens, with the overarching goal being to develop polarized brain organoids expressing region specific markers along a dorsoventral axis. In parallel, a coculture system incorporating both human meningeal cells and brain organoids was developed to enable studies of non-neuronal cell response to signaling from a brain organoid. In both 2D and 3D culture systems, meningeal cells remained viable; however, in the presence of a brain organoid meningeal cells exhibited unique migration behavior, resulting in eventual encapsulation of the organoid body. These findings contribute towards advancements in developing brain organoid systems that can more accurately model phenomena in the natural human brain.