“Poor regeneration is built into human neurons as they mature in the central nervous system.” That is the finding of George Gibbons, first author of a Cambridge study published in Cell Reports, and it explains why a broken spinal cord so rarely mends itself.
For families living with paralysis, the study offers something new: evidence that the block is not necessarily final.
Two tissues, one gap
A team led by Dr. András Lakatos at the University of Cambridge’s Department of Clinical Neurosciences built a miniature version of the pathway that drives movement. They had already made pea-sized organoids from patient-derived stem cells in 2021, shaped like parts of the human cerebral cortex, and used them to look at molecular faults in motor neurone disease.
This time the group grew brain organoids and spinal cord organoids separately, as the two structures are separate in the body. Nerve fibers then reached out of the brain tissue, crossed the space between, and joined the spinal cord tissue. The circuit worked well enough to make small clusters of muscle cells contract.
A cut-off point near day 150
The researchers kept these tiny nervous systems alive for over a year. Neurons could regrow injured axons, the long fibers that carry signals, up to about day 150 of development, roughly the middle of pregnancy. After that, the ability fell away sharply.
Gibbons described the contrast: “Neurons taken from less mature organoids regrew long fibers after injury, but those from more mature organoids showed a sharp drop in their ability to regrow.”
The team then studied gene activity in neurons linking brain and spinal cord, and found a network of genes that works like a switch. As neurons mature and form synapses, the network gradually limits axon growth. When the scientists blocked key regulators in it, the neurons grew axons again.
A drug already on pharmacy shelves
Next they searched a database of drug compounds for anything that could act on the same network. One candidate was lynestrenol, a hormone drug approved for some menstrual disorders and for contraception. Applied to damaged neurons, it increased axon regrowth significantly.
Lakatos was careful about what that means. “Lynestrenol itself may not be the answer to spinal cord repair,” he said, “but it shows us that, in principle, it should be possible to directly target human neurons and regenerate their axons.”
He added that the team still has to show the approach can restore the right connections between brain and spinal cord cells. “This gives us hope that one day we may be able to treat conditions previously thought untreatable.”
Scar tissue and inflammation also get in the way of repair after injury, and the researchers say neuron-specific barriers matter just as much. Earlier evidence suggests younger neurons can often send out axons even through the harsh environment at an injury site.
Why human tissue matters
Much of what is known about nerve regeneration comes from rodents, whose neurons behave differently. “Our sophisticated organoid models help bridge the knowledge gap from animal models to what we see in patients,” Lakatos said. He also pointed to their role in reducing the use of animals in research.
Cambridge groups are already using organoids to work on damaged livers, Crohn’s disease in children and the earliest stages of pregnancy. The study was funded by the UK Research and Innovation Medical Research Council and Spinal Research. Anyone with questions about their own condition should speak to their doctor.
