Exploring the prospects, advancements, and challenges of in vitro modeling of the heart-brain axis.

Research on bidirectional communication between the heart and brain has often relied on studies involving nonhuman animals. Dependance on animal models offer limited applicability to humans and a lack of high-throughput screening. Recently, the field of 3D cell biology, specifically organoid technology, has rapidly emerged as a valuable tool for studying interactions across organ systems, i.e., gut-brain axis. The initial success of organoid models indicates the usefulness of 3D cultures for elucidating the intricate interactivity of the autonomic nervous system and overall health. This perspective aims to explore the potential of advancing in vitro modeling of the heart-brain axis by discussing the benefits, applications, and adaptability of organoid technologies. We closely examine the current state of brain organoids in conjunction with the advancements of cardiac organoids. Moreover, we explore the use of combined organoid systems to investigate pathophysiology and provide a platform for treatment discovery. Finally, we address the challenges that accompany the use of 3D models for studying the heart-brain axis with an emphasis on generating tailored engineering strategies for further refinement of dynamic organ system modeling in vitro.