“That’s why paralysis is usually permanent.” Dr András Lakatos, a neuroscientist at the University of Cambridge, does not soften the point. When the nerve fibres that carry movement signals from the brain to the spinal cord are damaged, they rarely grow back. His team has now built a human model that shows when that ability fades, and that it can be switched on again.
The researchers started with stem cells taken from patients and guided them into small clumps of tissue called organoids, each about the size of a pea. One set resembled brain tissue. The other was spinal cord. The group, based in Cambridge’s Department of Clinical Neurosciences, reported the work in Cell Reports.
A circuit built in a dish
In the body, the brain and spinal cord are separate tissues linked by axons, the nerve fibre “cables” that pass signals along. So the team kept the two organoids apart. Fibres from the brain tissue grew across the gap and attached to the spinal cord tissue. The link worked well enough to make tiny clusters of muscle contract.
Lakatos had made his first “mini brains” in 2021, using them to study molecular problems in motor neurone disease. This is a bigger build: a small version of the connected human system.
The point where regrowth stops
The researchers kept the model alive for more than a year. Up to about day 150, which matches the mid-trimester of pregnancy, damaged axons could regrow. After that, growth was badly impaired.
George Gibbons, the study’s first author, put it plainly: “Neurons taken from less mature organoids regrew long fibres after injury, but those from more mature organoids showed a sharp drop in their ability to regrow. In other words, poor regeneration is built into human neurons as they mature in the central nervous system.”
By comparing gene activity in the neurons that join brain to spinal cord, the team found a network of genes acting as a switch on axon growth. Blocking key regulators of that network turned the growth ability back on.
An existing drug shows promise
The group then searched a database of drug compounds for any that act on those genes. One candidate was lynestrenol, a hormone drug licensed for certain menstrual disorders and as a contraceptive. On damaged neurons in the dish, it significantly boosted axon regrowth.
Lakatos is cautious about it. “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.” The team still has to show that regrown fibres make 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,” he added.
Scar tissue and inflammation may also block repair at an injury site, the Cambridge account notes. But evidence that younger neurons can grow through the hostile environment of an injury suggests the neurons themselves are worth targeting.
Why a human model matters
Most of what is known about nerve regeneration comes from rodents. “Their neurons behave differently from human neurons,” Lakatos said, and the organoids “help bridge the knowledge gap from animal models to what we see in patients.” He also pointed to the model as a way to cut the use of animals in research.
Traumatic spinal cord injury is the obvious target, but motor neurone disease and multiple sclerosis can also leave the central nervous system unable to repair itself. The loss can mean the inability to grasp or walk.
The work was funded by the UK Research and Innovation Medical Research Council and Spinal Research. Lakatos, a former PhD student funded by the charity, now sits on its Grant Advisory Board Committee. Spinal Research chief executive Louisa McGinn said the field was “entering a new era of hope and possibility for the 15million people worldwide living with a spinal cord injury.”
