A miniature model of the developing cerebral cortex, a brain region responsible for cognition, memory, and problem-solving, has been successfully cultivated in a laboratory setting. This cellular cluster now includes a network of blood vessels that closely mirrors its real-world counterpart. This organoid represents one of the most detailed brain models developed to date, poised to significantly enhance our comprehension of brain function.
Brain organoids, often referred to as “mini-brains,” are generally produced in laboratory dishes. This process involves culturing stem cells in a specially formulated mixture of chemical signals, which guides them to aggregate into cellular spheres. Since their initial creation in 2013, these cerebral structures, which bear resemblance to fetal or newborn brains, have offered valuable insights into neurological conditions such as autism, schizophrenia, and dementia.
However, a significant limitation of these organoids has been their tendency to degrade after a few months. Unlike fully developed brains, which are equipped with an intricate network of blood vessels for the delivery of oxygen and nutrients, lab-grown brain organoids rely solely on absorption from their surrounding dish. This restricted access to essential resources leads to the starvation of inner cells. Consequently, their size, complexity, and fidelity to the developing brain are constrained. “It’s a very big problem,” noted Lois Kistemaker from the University Medical Centre Utrecht Brain Centre in the Netherlands.
To overcome this challenge, Ethan Winkler and his team at the University of California, San Francisco, embarked on a two-month cultivation of human stem cells. The objective was to generate what they term “cortical organoids,” designed to emulate the developmental stages of the cerebral cortex. In parallel, they cultivated separate organoids composed of blood vessel cells. These vascular organoids were then strategically positioned at opposite extremities of each cortical organoid. Within a fortnight, the blood vessels had successfully permeated the entirety of the miniature brains.
A critical finding emerged from imaging the organoids: the blood vessels possessed a hollow interior, or lumen, bearing a striking resemblance to that found in actual brain vasculature. “The demonstration of vascular networks with lumens like you would find in actual blood vessels is impressive,” commented Madeline Lancaster from the University of Cambridge, who was instrumental in the initial development of brain organoids. “It’s a major step.”
Previous attempts to integrate blood vessels into brain organoids had faltered, failing to replicate this crucial feature and often resulting in uneven vessel distribution. Furthermore, the vessels in this recent experiment exhibited a closer approximation of the physical characteristics and genetic activity observed in genuine developing brains compared to earlier efforts. This led to the formation of an improved “blood-brain barrier,” the protective boundary that typically shields the brain from pathogens while facilitating the passage of nutrients and waste products, as Kistemaker explained.
Collectively, these results indicate a greater potential for the vessels to effectively transport nutrient-rich fluid, thereby sustaining the viability of the organoids, according to Lancaster. “To have truly functional [blood vessels], they would need a way to continuously pump blood through, like the heart does, and it would need to be in a directional manner, so fresh oxygenated blood – or a blood-like substitute – entering while deoxygenated blood is taken away,” Lancaster stated. “We are still a long way from that,” she added.