Paralysis after a spinal injury is usually permanent. The fibres that relay movement commands from the brain seldom grow back, and until recently nobody could say exactly when they lost the knack. A team at the University of Cambridge now has a fairly specific answer, and a hint that the loss need not be final.
“That’s why paralysis is usually permanent,” said Dr András Lakatos, the senior author, who works in the university’s department of clinical neurosciences. “But we didn’t know exactly when the ability of axons to regenerate becomes limited.” His group’s model, he said, suggests the block arrives during development and “can still be reversed after this point.”
A brain and spinal cord in a dish
Lakatos’s lab had already grown “mini brains” from human stem cells in 2021. This time the researchers built two organoids, one resembling brain tissue and one resembling spinal cord, and deliberately kept them apart, as they are in the body. Fibres from the brain tissue crossed the gap and linked up with the spinal tissue. The circuit worked: it could make small clusters of muscle contract.
The team kept the system alive for more than a year. Until about day 150, which matches the middle trimester of pregnancy, damaged axons regrew. After that, regrowth fell away sharply. George Gibbons, the first author, put it bluntly: “poor regeneration is built into human neurons as they mature in the central nervous system.”
The switch, and a drug
Gene expression analysis turned up a linked network of genes that seems to switch off axon growth once neurons mature and begin forming synapses. Blocking the key regulators of that network turned growth back on.
The researchers then searched a database of drug compounds for anything that acts on those genes. It returned lynestrenol, a hormone drug licensed as a contraceptive and for certain menstrual disorders. Applied to damaged neurons in the lab model, it boosted regrowth.
Nobody is suggesting a contraceptive will cure paralysis. Lakatos said lynestrenol “itself may not be the answer to spinal cord repair”, but that it shows human neurons can, in principle, be targeted directly to regenerate their axons. Scar tissue and immune cells also stand in the way of repair in a real injury, so the neuron’s own switch is only part of the problem. And the team still has to show that regrown fibres can restore proper connections between brain and spinal cord.
Why a human model matters
Rodents supply most of the existing data on nerve regeneration, and their neurons do not behave quite like ours. “Our sophisticated organoid models help bridge the knowledge gap from animal models to what we see in patients,” Lakatos said in a statement. He added that the models also reduce how many animals researchers need.
Axons that fail to regrow also feature in multiple sclerosis and motor neurone disease, so a switch that can be flipped could matter well beyond spinal injury. The work appeared in Cell Reports, and Lakatos’s own verdict was measured: “this gives us hope that one day we may be able to treat conditions previously thought untreatable.”
Sources
- Lab-Grown Brains Could One Day Help Reawaken Nerve Regeneration
- 'Irreversible' spinal cord damage may be reversed, research suggests
