Emerging approaches to enhance human brain organoid physiology.

Brain organoids are important 3D models for studying human brain development, disease, and evolution. To overcome some of the existing limitations that affect organoid quality, reproducibility, characteristics, and in vivo resemblance, current efforts are directed to improve their physiological relevance by exploring different, yet interconnected, routes. In this review, these approaches and their latest developments are discussed, including stem cell optimization, refining morphogen administration strategies, altering the extracellular matrix (ECM) niche, and manipulating tissue architecture to mimic in vivo brain morphogenesis. Additionally, strategies to increase cell diversity and enhance organoid maturation, such as establishing co-cultures, assembloids, and organoid in vivo xenotransplantation, are reviewed. We explore how these various factors can be tuned and intermingled and speculate on future avenues towards even more physiologically-advanced brain organoids.