In a study published in the journal cell stem cell On February 2, researchers show that brain organoids — clumps of lab-grown neurons — can integrate into rat brains and respond to visual stimulation like flashing lights.
Decades of research has shown that we can transplant single human and rodent neurons into rodent brains, and more recently it has been shown that human brain organoids can integrate into developing rodent brains. However, whether these organoid grafts can be functionally integrated into the visual system of injured adult brains remains to be investigated.
“We focused on not just transplanting single cells, but actually transplanting tissue,” says senior author H. Isaac Chen, physician and assistant professor of neurosurgery at the University of Pennsylvania. “Brain organoids have an architecture; they have a structure that resembles the brain. We were able to look at individual neurons within this structure to gain a deeper understanding of the integration of transplanted organoids.”
The researchers cultured neurons derived from human stem cells in the lab for about 80 days before transplanting them into the brains of adult rats that had suffered injuries to their visual cortex. Within three months, the transplanted organoids had integrated into their host’s brain: they became vascularized, increased in size and number, emitted neuronal projections, and formed synapses with the host’s neurons.
The team used fluorescently tagged viruses that jump from neuron to neuron at synapses to detect and track physical connections between the organoid and the host rat’s brain cells. “By injecting one of these viral tracers into the animal’s eye, we were able to trace the neuronal connections downstream of the retina,” says Chen. “The tracer made it to the organoid.”
Next, the researchers used electrode probes to measure the activity of individual neurons within the organoid when the animals were exposed to blinking lights and alternating white and black bars. “We saw that a large number of neurons within the organoid responded to specific directions of light, giving us evidence that these organoid neurons were not only able to integrate into the visual system, but also very specific functions of the visual cortex.”
The team was surprised at the extent to which the organoids were able to integrate in just three months. “We didn’t expect to see this level of functional integration so early,” says Chen. “There have been other studies looking at single cell transplantation that show that even 9 or 10 months after you transplant human neurons into a rodent, they’re still not fully mature.”
“Neural tissues have the potential to rebuild areas of the injured brain,” says Chen. “We haven’t worked everything out yet, but this is a very solid first step. Now we want to understand how organoids can be used in other areas of the cortex, not just the visual cortex, and we want to understand the rules for controlling how organoid neurons integrate into the brain so that we can better control and speed up this process. “