Human stem cell-derived tissue transplanted into rats show potential for repairing damaged brains

Scientists have successfully shown that human brain tissue can integrate with rat brains and allow the rat to respond to visual stimuli like flashing lights.

Earlier research has shown that individual human and rodent neurons can be transplanted into rat brains, and that human brain organoids can integrate into developing rodent brains.

But this is the first study to investigate whether brain organoid grafts can functionally integrate with the visual system of injured adult brains.

“We focused on not just transplanting individual cells, but actually transplanting tissue,” says Han-ChiaoIsaac Chen, a physician, Assistant Professor of Neurosurgery at the University of Pennsylvania in the US, and senior author of the study published in Cell Stem Cell.

“Brain organoids have architecture; they have 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.”

Injuries to the cerebral cortex (the outer, wrinkled layer of the brain), like those caused by traumatic brain injury and stroke, can cause long-term neurological disability.

Regenerative medicine raises the possibility of one day repairing that damage by transplanting patient-matched neural tissues to the site of damage, using brain organoids grown from human pluripotent stem cells.

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In this study, researchers cultivated human stem cells into brain organoids for about 80 days before grafting them into a small cavity made in the visual cortex of adult male rats.

Within three months, the grafted organoids had integrated with their host’s brain: growing blood vessels, growing in size and number, sending out neuronal projections, and forming synapses with the host’s neurons.

They were able to detect and trace the physical connections between the organoid and the brain cells of the rat by injecting fluorescent-tagged viruses – modified rabies virus (RABV) and modified herpes simplex virus (HSV) – that can move along synapses from neuron to neuron.

“By injecting one of these viral tracers into the eye of the animal, we were able to trace the neuronal connections downstream from the retina,” says Chen.

“The tracer got all the way to the organoid.”

Then they used electrode probes to measure the activity of individual neurons in the brain organoid while the rats were exposed to flashing lights and alternating white and black bars.

“We saw that a good number of neurons within the organoid responded to specific orientations of light, which gives us evidence that these organoid neurons were able to not just integrate with the visual system, but they were able to adopt very specific functions of the visual cortex,” explains Chen.

“We were not expecting to see this degree of functional integration so early. There have been other studies looking at transplantation of individual cells that show that even 9 or 10 months after you transplant human neurons into a rodent, they’re still not completely mature.”

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The authors write that, although the cavity created prior to organoid transplantation was a significant brain injury, it doesn’t reflect the outcomes of disorders such as traumatic brain injury and stroke. However, their work does provide proof of principle that brain organoid grafts could integrate with injured adult mammalian brains.

“Neural tissues have the potential to rebuild areas of the injured brain. We haven’t worked everything out, but this is a very solid first step,” says Chen.

“Now, we want to understand how organoids could be used in other areas of the cortex, not just the visual cortex, and we want to understand the rules that guide how organoid neurons integrate with the brain so that we can better control that process and make it happen faster.”