Excellence in Research: Human Stem Cell-Derived Polarized Dorsoventral Forebrain Organoid: Effect of Matrix Stiffness and Mechanical Stimulus

This award will support research that advances our understanding of the biophysical cues that determine stem cell fate. All tissues and organs are derived from stem cells, and a complex array of signals influence the development of stem cells into specific tissue types. The “fate” of a stem cell, which means the specific cell type it ultimately becomes, depends on cues to the cells during organ development.

These cues can be biochemical, biophysical or a combination. This work will focus on the development of the brain and the biophysical signals that influence this process. This work will use “organoids” – small three-dimensional cellular structures grown in a lab to mimic the physiology and function of the full-sized organ.

Many studies have used brain organoids to examine the biochemical cues that influence the development of stem cells into brain tissue. However, relatively few have studied the biophysical regulation of stem cell differentiation under both static (constant) and dynamic (varying) stimuli. This work will first develop a micro-device to generate consistent and controllable static and dynamic forces.

This device will be used to characterize the mechanobiology of organ development. Understanding the mechanical cues that determine the brain organoid’s stem cell fate can ultimately provide new opportunities for studying neurological or neurodegenerative disorders, personalized treatment, cancer, and the effects and treatments of traumatic brain injury.

This research involves several disciplines, including micro-device development, mechanobiology, stem cell engineering, materials science, and computational medicine. This project will ultimately advance our knowledge of brain tissue engineering, regenerative medicine, biomanufacturing, and pharmacology, and will be of significant interest to the next-frontier workforce, leading to the clinical and industrial success of such engineering systems

Understanding the roles of the biological cues that regulate lineage-specific differentiation of stem cells is critical to the development of polarized organoid structures. However, much of the current literature has focused on the role of biochemical stimuli to generate region-specific brain organoids, rather than on biophysical stimuli, the focus of this work.

This work will address this imbalance by discovering how morphogenetic chemicals, extracellular matrix (ECM) stiffness, and mechanical stimuli affect the development of dorsoventral polarized and cortical forebrain organoids in a spatiotemporal manner. This work will provide new knowledge addressing the roles of soluble morphogenetic factors and gradients, ECM mechanics, mechanical stimuli, and signaling pathways in seamlessly regulating organoid differentiation and organization.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.