Basic models to advanced systems: harnessing the power of organoids-based microphysiological models of the human brain

Abstract

Abstract Understanding the complexities of the human brain’s function in health and disease is a formidable challenge in neuroscience. While traditional models like animals offer valuable insights, they often fall short in accurately mirroring human biology and drug responses. Moreover, recent legislation has underscored the need for more predictive models that more accurately represent human physiology. To address this requirement, human-derived cell cultures have emerged as a crucial alternative for biomedical research. However, traditional static cell culture models lack the dynamic tissue microenvironment that governs human tissue function. Advanced in vitro systems, such as organoids and microphysiological systems (MPSs), bridge this gap by offering more accurate representations of human biology. Organoids, which are three-dimensional miniaturized organ-like structures derived from stem cells, exhibit physiological responses akin to native tissues, but lack essential tissue-specific components such as functional vascular structures and immune cells. Recent endeavors have focused on incorporating endothelial cells and immune cells into organoids to enhance vascularization, maturation, and disease modeling. MPS, including organ-on-chip technologies, integrate diverse cell types and vascularization under dynamic culture conditions, revolutionizing brain research by bridging the gap between in vitro and in vivo models. In this review, we delve into the evolution of MPS, with a particular focus on highlighting the significance of vascularization in enhancing the viability, functionality, and disease modeling potential of organoids. By examining the interplay of vasculature and neuronal cells within organoids, we can uncover novel therapeutic targets and gain valuable insights into disease mechanisms, offering the promise of significant advancements in neuroscience and improved patient outcomes.